Cellular and molecular aspects of diabetic nephropathy; the role of VEGF-A

array:19 ["pii" => "X2013251415119105" "issn" => "20132514" "estado" => "S300" "fechaPublicacion" => "2015-03-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2015;35:131-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 10413 "formatos" => array:3 [ "EPUB" => 342 "HTML" => 8406 "PDF" => 1665 ] ] "itemSiguiente" => array:15 [ "pii" => "X2013251415119180" "issn" => "20132514" "estado" => "S300" "fechaPublicacion" => "2015-03-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2015;35:139-45" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 6071 "formatos" => array:3 [ "EPUB" => 323 "HTML" => 5103 "PDF" => 645 ] ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "Hypertension in the African American population: A succinct look at its epidemiology, pathogenesis, and therapy" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "139" "paginaFinal" => "145" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Hipertensión en la población afroamericana: breve examen de su epidemiología, patogénesis y terapia" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "498v35n02-90411918fig3.jpg" "Alto" => 1200 "Ancho" => 2037 "Tamanyo" => 210277 ] ] "descripcion" => array:1 [ "en" => "– Treatment of hypertension in African Americans vs Whites. a Albumin:creatinine >200 mg/g, eGFR <60 ml min 1 73 m2 left ventricular hypertrophy by electro-echocardiogram b heart failure cad peripheral arterial disease stroke tia abdominal aortic aneurysm c calcium channel antagonist d renin angiotensin or at1 receptor blocker e agents are used with compelling indications</60>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Luis M Ortega, Emad Sedki, Ali Nayer" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Luis M" "apellidos" => "Ortega" ] 1 => array:2 [ "nombre" => "Emad" "apellidos" => "Sedki" ] 2 => array:2 [ "nombre" => "Ali" "apellidos" => "Nayer" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251415119180?idApp=UINPBA000064" "url" => "/20132514/0000003500000002/v0_201504231604/X2013251415119180/v0_201504231605/en/main.assets" ] "itemAnterior" => array:15 [ "pii" => "X2013251415119090" "issn" => "20132514" "estado" => "S300" "fechaPublicacion" => "2015-03-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2015;35:127-30" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 5938 "formatos" => array:3 [ "EPUB" => 332 "HTML" => 4835 "PDF" => 771 ] ] "en" => array:9 [ "idiomaDefecto" => true "titulo" => "Reflections on two consensus documents about chronic kidney disease" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "127" "paginaFinal" => "130" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Reflexiones a propósito de dos documentos de consenso sobre enfermedad renal crónica" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Alberto Martínez-Castelao, Manuel Gorostidi, José Luis Górriz, Rafael Santamaría Olmo, Jordi Bover, Julián Segura" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Alberto" "apellidos" => "Martínez-Castelao" ] 1 => array:2 [ "nombre" => "Manuel" "apellidos" => "Gorostidi" ] 2 => array:2 [ "nombre" => "José Luis" "apellidos" => "Górriz" ] 3 => array:2 [ "nombre" => "Rafael" "apellidos" => "Santamaría Olmo" ] 4 => array:2 [ "nombre" => "Jordi" "apellidos" => "Bover" ] 5 => array:2 [ "nombre" => "Julián" "apellidos" => "Segura" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251415119090?idApp=UINPBA000064" "url" => "/20132514/0000003500000002/v0_201504231604/X2013251415119090/v0_201504231605/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "titulo" => "Cellular and molecular aspects of diabetic nephropathy; the role of VEGF-A" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "131" "paginaFinal" => "138" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Katherine Carranza, Dolores Veron, Alicia Cercado, Noemi Bautista, Wilson Pozo, Alda Tufro, Delma Veron" "autores" => array:7 [ 0 => array:3 [ "nombre" => "Katherine" "apellidos" => "Carranza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 1 => array:3 [ "nombre" => "Dolores" "apellidos" => "Veron" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] 2 => array:3 [ "nombre" => "Alicia" "apellidos" => "Cercado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] 3 => array:3 [ "nombre" => "Noemi" "apellidos" => "Bautista" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] 4 => array:3 [ "nombre" => "Wilson" "apellidos" => "Pozo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "affd" ] ] ] 5 => array:3 [ "nombre" => "Alda" "apellidos" => "Tufro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "affe" ] ] ] 6 => array:3 [ "nombre" => "Delma" "apellidos" => "Veron" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "School of Medicine, School of Medical Sciences, Universidad de Guayaquil [University of Guayaquil]. Guayaquil, Guayas (Ecuador)" "etiqueta" => "a" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "School of Social Work, School of Law and Social Sciences, Universidad Nacional de Córdoba [National University of Córdoba], Córdoba, Córdoba (Argentina)" "etiqueta" => "b" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "School of Health Sciences, Universidad Estatal de Milagro [State University of Milagro], Milagro, Guayas (Ecuador)" "etiqueta" => "c" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "School of Natural Sciences, Universidad de Guayaquil, Guayaquil. Guayas (Ecuador)" "etiqueta" => "d" "identificador" => "affd" ] 4 => array:3 [ "entidad" => "Department of Paediatrics, School of Medicine, Yale University, New Haven, Connecticut (USA)" "etiqueta" => "e" "identificador" => "affe" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Aspectos celulares y moleculares de la nefropatía diabética, rol del VEGF-A" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "498v35n02-90411910fig1.jpg" "Alto" => 750 "Ancho" => 908 "Tamanyo" => 74235 ] ] "descripcion" => array:1 [ "en" => "– In Ecuador, mortality caused by diabetes mellitus was higher in the provinces of Guayas, Los Ríos and Manabí, located on the Pacific coast. Map shows the mortality rate due to diabetes mellitus (deaths/100,000 individuals per year, INEC [Instituto Nacional de Estadísticas y Censos - National Institute of Statistics and Census of Ecuador] 2011). This figure is part of a figure originally published by Neira-Mosquera et al.6, with minor modifications (authorised reproduction)." ] ] ] "textoCompleto" => "Issue relevance The prevalence of diabetes mellitus has increased worldwide since the last century1. In adults aged between 20 and 79 years of age, its prevalence reaches 8%1. Diabetes spreads through rich and poor countries, but it is prevalent in vulnerable groups and lower-income regions of the world. Territories showing the highest numbers of affected individuals are: China, India, the United States, Brazil and Russia1. This situation is associated with greater urbanisation, low socioeconomic level, inequality, increased life expectancy and population density, ethnic factors, nutrition, physical inactivity, and being overweight1,2. In Spain, a diabetes prevalence rate of 13.8% was reported, while 6.8% had not yet been diagnosed3. Recent estimates suggest that worldwide prevalence will have doubled by 2035, while in our region, South America and Central America, it will have increased to 9.8%1,2. In addition, 45.5% of individuals with diabetes will not be diagnosed with the disease1,2. In the urban population located on the coasts of our region, diabetes prevalence is higher than in the mountains or the jungle, and the same happens with people who move from the rural to the urban environment1-2. Moreover, native populations are particularly vulnerable due to the change in lifestyle, marginalisation and lower exposure to health care systems2. In Ecuador, the prevalence of diabetes is 6%, and in 2010 it was the second cause of mortality2,4,5. In the provinces of Guayas, Los Ríos and Manabí, located on the Pacific coast, the mortality rate due to diabetes and industrialised food consumption is higher; meanwhile, in the Amazon, natural food-based nutrition predominates and the rate is lower6 (Figure 1).<img alt="Figure 1 – In Ecuador, mortality caused by diabetes mellitus was higher in the provinces of Guayas, Los Ríos and Manabí, located on the Pacific coast. Map shows the mortality rate due to diabetes mellitus (deaths/100,000 individuals per year, INEC [Instituto Nacional de Estadísticas y Censos - National Institute of Statistics and Census of Ecuador] 2011). This figure is part of a figure originally published by Neira-Mosquera et al.6, with minor modifications (authorised reproduction)." src="498v35n02-90411910fig1.jpg"></img>Figure 1 – In Ecuador, mortality caused by diabetes mellitus was higher in the provinces of Guayas, Los Ríos and Manabí, located on the Pacific coast. Map shows the mortality rate due to diabetes mellitus (deaths/100,000 individuals per year, INEC [Instituto Nacional de Estadísticas y Censos - National Institute of Statistics and Census of Ecuador] 2011). This figure is part of a figure originally published by Neira-Mosquera et al.6, with minor modifications (authorised reproduction). Kidney disease caused by diabetes is called diabetic nephropathy (DN). About 30% of patients with diabetes develop DN7,8. Such disease is the main cause of chronic kidney disease (CKD) and of admission to dialysis7-11. The increase in adult diabetes has been recorded in the last few decades, and CKD affects 10% to 16% of adults, which constitutes a serious worldwide problem7-11. In South America, the prevalence of diabetes and end-stage CKD (ECKD) has increased in recent decades, and access to dialysis varies greatly among these countries9-11. In Ecuador, the prevalence of patients who received renal function replacement therapy in 2010 was 406 individuals per one million inhabitants11. On the other hand, the renin-angiotensin-aldosterone system (RAAS) inhibitors constitute the best therapeutic option for DN, but the residual risk of ECKD continues to be high and the association of these drugs was related to hyperpotassemia and acute kidney failure (AKF)12-13. The search for new therapeutic alternatives is necessary. Population studies raise awareness of the problem, while the knowledge generated in research laboratories expand our understanding of the biological events that occur in individuals. In this review, we will include anatomical and patho-physiological concepts that reveal the crucial importance of events occurring at the glomerular level. In addition, we will analyse the role played by the vascular endothelial growth factor (VEGF-A) and its relationships with nitric oxide (NO), the insulin receptor and angiopoietins. Finally, we will consider basic aspects and the analyses of recently published molecular and cellular studies.Anatomical and pathophysiological aspects of DN Diabetes involves functional and structural kidney alterations that induce proteinuria at variable magnitudes, ranging from micrograms to several grams per day7,8,13. The risk of developing ECKD is related to albumin urinary excretion, and early detection of RAAS inhibitors is important due to the beneficial renal and systemic effects7,8,13. DN is accompanied by persistent albumin urinary excretion or microalbuminuria, which is defined as the loss of urinary albumin ranging from 20 to 199 µg/min or 30 to 299 mg/d on two different occasions and when the albumin/creatinine ratio is 30-299 mg/g in an isolated urine sample7,8. In type 1 diabetes, albumin urinary excretion should be quantified on an annual basis, from the fifth year following diagnosis onwards; in type 2 diabetes, given the difficulty to accurately state its onset, measurement is preferable from the moment the disease is diagnosed7,8. In one study, the prevalence of microalbuminuria in patients with type 2 diabetes was 24.9% after a ten-year follow-up14, but 30% of patients with type 2 diabetes and no microalbuminuria developed DN. It is also important to quantify glomerular filtration (GF), since some patients only show renal function impairment with no signs of proteinur ia7,8. Considering that 85% of the patients with diabetes have type 2 diabetes, better biomarkers are required7,8,13,14. Risk factors contributing to the development of DN are hyperglycaemia, hypertension (HTN), dyslipidaemia, age over 65 years, male gender, smoking habit, family history and Hispanic or Afro-American origin7,8. Familial clustering was reported in populations with different ancestors, especially in Pima Indians and Afro-Americans16. Mooyaart et al. found 24 genetic variations associated with DN17. Epigenetic mechanisms were also implied8,18. For example, chronic hyperglycaemia, without altering the nucleotide sequence, may modify DNA or methylate histones associated with DNA18. However, the significance of these findings on the development of DN has not been determined yet. Many factors were implied in DN pathophysiology, such as: glucose, glucose receptors, VEGF-A, NO, reactive oxygen species (ROS), transforming growth factor beta (TGF-Beta), RAAS, kinin-kallikrein system, mammalian target of rapamycin, inflammation, tumour necrosis factor alpha, adiponectin, advanced glycation end products and receptors thereof, mitochondr ial oxidat ive stress and micro-RNA7,8,15,19,20-22. From the pathologic point of view, type 1 and type 2 diabetes induce common kidney lesions. These lesions were characterised in type 1 diabetes7,8,15,23-26. In type 2 diabetes, the kidney histology and course have special features, associated with comorbidities such as HTN, vascular diseases, ageing and obesity7,8,23-24. Five years after diabetes diagnosis, there is hyperfiltration, microalbuminuria, glomerulomegaly, glomerular basal membrane (GBM) thickening and alteration of podocytes26. Subsequently, the extracellular matrix (ECM) is deposited in the mesangium. Approximately ten years later, proteinuria and HTN are evident, and GF becomes progressively impaired7,23,24,26. Within a period of 20 to 25 years, sclerosis is advanced, there is tubulointerstitial fibrosis and CKD progresses to end-stage phases7,24-26. Meanwhile, the glomeruli, tubules, interstitium and renal arteries are modified by the diabetic environment. Glomerular changes involve the glomerular filtration barrier (GFB), ECM, and the main cells composing it (podocytes, endothelial cells and mesangial cells)7,16,19-21-25. In addition, it prevents the abnormal passage of plasma protein based on size and load, and its alteration was associated with proteinuria7,15,19,20,25. The GFB is composed of podocytes, GBM, and the endothelium (Figure 2). Podocytes are markedly differentiated epithelial cells, with a large cell body, and primary and secondary extensions connected by slit diaphragms (SD)15,19,20. The SD is permeable to water and small solutes, but it is selective to large molecule passage, which is a key factor in GFB permeability25. Moreover, it is composed of a protein complex, where nephrin plays an important role7,15,19,20. On the apical side, podocytes float within the urinary space, while on the baso-lateral side, they make contact with the GBM. Podocyte cytoskeleton proteins are related to GBM proteins through integrins and dystroglycans15,20,25. The GBM is mainly composed of proteins, such as collagen IV and laminins15,25. The fenestrated endothelium, covered by glycocalyx, is the inner most layer of the GFB7,15,21,25. Diabetes alters the three layers that make up the GFB. Among the early changes, neoangio-genesis in the glomerular vascular pole and loss of endothelial fenestrations have been described7,16,22,23. The GBM shows an increased thickness due to protein exchange alterations7,15,19,20,25. In podocytes, f lattening, hypertrophy, detachment and apoptosis are observed in the early stages, while later podocytopenia is observed7,15,19,20.<img alt="Figure 2 – Schematic representation of the glomerulus, the glomerular filtration barrier (GFB) composed of podocytes (P), the glomerular basal membrane (GBM), and the endothelium. Plasma ultrafiltration passes through the GFB (black arrow) to reach the urinary space (US). Podocytes (green) make contact with several glomerular capillaries (represented as red circles) and the intraglomerular mesangium (M). The GBM (black line) wraps the capillaries and surrounds the mesangium. The glomerular endothelium is represented by a discontinuous light-blue line, located between the capillary lumen (CL) and the GBM, the vascular pole in the lower part of the glomerulus, the tubular pole in the upper part. B: Ultrastructure of the GFB observed with an electronic microscope: podocytes, GBM, slit diaphragm (SD) and fenestrated endothelium. Plasma ultrafiltration passes through the GFB (yellow arrow) from the capillary lumen (CL) towards the urinary space (US)." src="498v35n02-90411910fig2.jpg"></img>Figure 2 – Schematic representation of the glomerulus, the glomerular filtration barrier (GFB) composed of podocytes (P), the glomerular basal membrane (GBM), and the endothelium. Plasma ultrafiltration passes through the GFB (black arrow) to reach the urinary space (US). Podocytes (green) make contact with several glomerular capillaries (represented as red circles) and the intraglomerular mesangium (M). The GBM (black line) wraps the capillaries and surrounds the mesangium. The glomerular endothelium is represented by a discontinuous light-blue line, located between the capillary lumen (CL) and the GBM, the vascular pole in the lower part of the glomerulus, the tubular pole in the upper part. B: Ultrastructure of the GFB observed with an electronic microscope: podocytes, GBM, slit diaphragm (SD) and fenestrated endothelium. Plasma ultrafiltration passes through the GFB (yellow arrow) from the capillary lumen (CL) towards the urinary space (US). Recently published articles that relate VEGF-A to glomerular proteins involved in human and experimental DN pathophysiogenesis are analysed below. Throughout the text, we will suggest several pathways which may be used to generate new therapeutic tools (Table 1).<img alt="Table 1 – Glomerular pathways with therapeutic potential for DN" src="498v35n02-90411910fig3.jpg"></img>The role of VEGF-A in DN VEGF-A is a potent angiogenic factor related to normal and pathological angiogenesis. It promotes the proliferation, differentiation and migration of endothelial cells; it induces vasodilation and increases vascular permeability15,19,20,27. It plays an important role in kidney development; in the adult kidney, it is secreted by podocytes and is essential for the maintenance of the GFB15. It acts through tyrosine-kinase receptors, which are known as VEGF receptor 1 and 2 (VEGFR1 and 2)15,27. VEGFR2 is expressed in endothelial cells and podocytes; it is related to the most important signals of VEGF-A15,27. Two co-receptors called neuropilins 1 and 2 amplify the VEGFR2 signal15.27. There is evidence that glucose directly and indirectly stimulates VEGF-A expression in podocytes through angiotensin II and TGF-Beta15,19,20. Glucose plays a very important role in DN pathophysiogenesis. Glycaemic control reduces DN progression and induces reversion of proteinuria and advanced histological lesions28-32. In a 30-year follow-up study, proteinuria, GF and HTN showed an improvement in patients with type 1 diabetes when there was better glycaemic control28. With a higher control of hyperglycaemia, GBM has shown less thickening29. Histological changes of advanced DN reverted 10 years after pancreas transplantation30. Haraguchi et al. were able to revert nephrotic-range proteinuria and histological lesions compatible with advanced DN after five years of intensive treatment of hyperglycaemia31. Treatment with bariatric surgeries administered to patients with type 2 diabetes and obesity improved GF and proteinuria, which was related to weight loss and decreased hyperglycaemia32. Hyperglycaemia increases renin and angiotensinogen expression in mesangial cells20. Mesangial cells and podocytes synthesise angiotensin II and express angiotensin receptors19,20. The increase in angiotensin II stimulates the expression of TGF-Beta, VEGF-A, connective tissue growth factor (CTGF), interleukin 6 and chemoattractant protein for monocytes-1 inducing expansion of the ECM and podocyte apoptosis7,15,19,20. In addition, glucose increases TGF-Beta expression in mesangial cells and podocytes19. Active TGF-Beta induces GBM thickening and glomerulosclerosis through the VEGF and CTGF; the increase in VEGF-A inhibits TGF-Beta expression, in a negative feedback mechanism15,19,20. In contrast, the increase in VEGF-A in diabetes is associated with elevated TGF-Beta and CTGF, proliferation and build-up of proteins in the glomerular ECM15,19,20. TGF-Beta has been related to the proliferation of mesangial cells, diffuse nodular glomerulo-sclerosis and also fibrosis15,19,20. In transgenic mice with no TGF-Beta type 2 receptor, the administration of anti-TGF-Beta antibodies prevented mesangial build-up and kidney function impairment19,20. These antibodies represent a therapeutic hope for DN, but they are not available for human use yet19.Glomerular VEGF-A modifications in DN Starting from early DN stages, systemic and renal VEGF-A are elevated in humans and mice, and they have also been associated with neoangigenesis15,21,22. RAAS, VEGF-A and nephrinuria were seen to be involved in this process15,19,20,22,33-38, while cultured podocytes and endothelial cells increased VEGF-A and VEGFR2 expression in response to the increase in glucose39-41. We showed that glomerular VEGF is a key factor for DN development and progress33-34. Normoglycaemic mice with VEGF overexpression in podocytes developed glomerulomegaly, hyperfiltration, GBM thickening and podocyte lesion, which are changes similar to early DN33. In these transgenic mice, diabetes caused massive proteinuria, advanced nodular glomerulosclerosis and less nephrin expression34. Diabetic mice with no VEGF overexpression only showed mild diffuse glomerulosclerosis34. These experiments show that the increase in glomerular VEGF, irrespective of the diabetic environment, generates identical changes in early DN and that increasing glomerular VEGF speeds up DN progress to more advanced stages. In the absence of diabetes, the urinary VEGF-A was reported to be a good marker of VEGF glomerular expression and it correlated with proteinuria33. Contrarily, in the case of diabetes, VEGF-A has not been observed to be a good marker of glomerular expression or DN severity. Urine and systemic VEGF-A levels were high in diabetic mice with and without glomerular VEGF overexpression34. Probably, within the diabetes context, urinary excretion of VEGF-A reflects systemic levels, while hiding VEGF glomerular changes34. In short, these experiments suggest that glomerular VEGF-A is a determining factor in DN, that VEGF overexpression in podocytes is dangerous, and that glucose directly and indirectly stimulates the VEGF-A signalling cascade in podocytes. In diabetes, urinary and systemic VEGF-A did not correlate with either glomerular VEGF expression or with the severity of glomerular lesions, which brings into question the use of VEGF-A as a DN biomarker. Glomerular VEGF-A reduction was shown to generate GFB lesions, proteinuria and kidney failure in animals and humans42,43. Transgenic mice with silencing of VEGF-A in podocytes showed AKF, alteration of the three GFB layers and reduced integrin expression43. Some patients treated with anti-VEGF-A antibodies showed proteinuria, endothelial lesions and thrombotic microangiopathy42. This evidence suggests that VEGF-A released by podocytes is important for the maintenance of the function and the glomerular structure in the adult kidney. Whether glomerular VEGF-A expression control improves DN has not yet been determined, but there is evidence that shows contradictory results. Administration of anti-VEGF antibodies improved DN in rodents44. In experiments conducted in mice, endostatin and tumstatin prevented the development of DN due to a decrease in VEGF-A and angiopoietin 236. In contrast, diabetic mice with gene deletion of VEGF-A in podocytes showed proteinuria and severe diffuse glomerulosclerosis associated with endothelial injury and apoptosis42. The evidence described herein suggests that close monitoring of glomerular VEGF-A levels in diabetes is required in order to avoid adding new lesions or worsening DN. Monitoring glomerular VEGF-A expression within very close margins may have a therapeutic potential, but the optimal concentrations and the right moment to perform such manipulation have not yet been defined.VEGF-A relationships with insulin receptors, nephrin and ROS in DN In DN, glomeruli with different lesion degrees coexist; VEGF-A expression and its signalling cascade have been related to glomerular changes37. In biopsies of patients with DN, there has been evidence of a higher VEGF expression in the glomeruli with lesions due to diabetes than in intact glomeruli37. However, VEGF-bound receptor expression was seen to be elevated in glomeruli with mild lesions and decreased in glomeruli with moderate or severe compromise37. A similar behaviour was observed with phosphorylation of serine/threonine protein kinase, a protein located in the VEGF signalling cascade, which suggested that other factors would modulate VEGF/VEGFR activity37. Podocytes express insulin receptors, whose activity depends on nephrin expression45,46. Insulin receptors are located in the SD, where podocytes express nephrin and VEGFR233,46. We have characterised the existing interaction between nephrin and VEGFR216. VEGF overexpression in podocytes was found to decrease nephrin expression and phosphor ylation16,33. Hale et al. reported that insulin increases VEGF-A production in podocytes, both in humans and mice45. In transgenic mice, this VEGF-A increase was disrupted by insulin resistance, anticipating the development of podocyte lesions secondary to insulin resistance45. In patients with insulin resistance caused by diabetes and by other diseases, kidney alterations, such as hyperfiltration, proteinuria, modifications in FGB and mesangium were described47,48. Jointly, these findings suggest that VEGF, nephrin and insulin receptor may be related to DN and insulin resistance, thus constituting glomerular pathways susceptible to being modified. Furthermore, oxidative stress secondary to hyperglycaemia may modify glycocalyx, increase ROS and advanced glycation end products, and alter the endothelium. In addition, protein kinase C (PKC) glomerular activation was associated with mesangial expansion, GBM thickening, endothelial dysfunction, cytokine and TGF-Beta activation7,15,21,40,41. Mima et al. described that hyperglycaemia alters nephrin phosphorylation in diabetic rats and cultured podocytes exposed to high concentrations of glucose49. Nephrin phosphorylation interruption was attributed to a “glomerular VEGF resistance” status related to PKC activation49. The VEGF signalling cascade in podocytes and endothelial cells was selectively inhibited by hyperglycaemia49. The increase in glucose and diabetes would cause higher podocyte apoptosis and endothelial dysfunction, partly due to a higher activation of mitogen-activated protein kinase (PKCδ/p38) and SRc homology-2-domain-containing phosphatase-1 (SHP-1) overexpression49. In addition, SHP-1 negatively regulates VEGFR2 and the insulin receptor49. Warren et al. showed that hyperglycaemia reduces endothelial VEGFR2 activity in diabetes41. ROS generation caused by hyperglycaemia was observed to induce VEGFR2 activation and its subsequent breakdown, notwithstanding the VEGF-A41. This would alter the normal response of endothelial cells to circulating VEGF-A due to lower receptor availability. By blocking ROS production with antioxidants, VEGFR2 availability and the lack of endothelial response to VEGF-A caused by hyperglycaemia were reverted41. These results suggest that the increase in VEGF-A present from early stages of DN may be secondary to “VEGF-resistance” of the VEGFR2 caused by higher receptor breakdown in endothelial cells. Jointly, these publications indicate that, in DN, VEGF over-expression in podocytes may be stimulated in an autocrine and paracrine way by a “VEGF-resistance” state. VEGF-A connections with oxidative stress at glomerular level may represent pathways with therapeutic potential.Relationship between angiopoietins and VEGF-A in DN Angiopoietins, which are growth factors involved in angio-genesis, have been related to DN15,36. Plasma levels of angiopoietin 2 are high in diabetic humans and mice, thus altering the angiopoetin-1/angiopoetin-2 ratio. Diabetic mice with lower angiopoietin 1 levels showed aberrant angiogenesis, hyperfiltration, glomerulomegaly and albuminuria, accompanied by VEGF-A and phosphorylated VEGFR2 overexpression. Alterations caused by reduced angiopoietin 1 were seen to be partially prevented by restoring its expression in podocytes in transgenic mice36. These experiments show the importance of angiopoietins and their relationship with VEGF-A in DN pathophysiogenesis. Modification of protein expression at the glomerular level (by manipulating the cells that produce these proteins) is a therapeutic alternative36.Relationship between VEGF-A and nitric oxide in DN VEGF-A stimulates NO production by means of endothelial NO synthase (eNOS) activation15,35.50. The effects of VEGF-A on vasodilation and on the vascular permeability increase are mediated by the increase in eNOS-dependent NO15,27,35,50. Under normal conditions, VEGF-A induces eNOS activation and an increase in NO; this increase negatively regulates VEGF-A and CTGF, inhibiting ECM build-up15. In diabetes, this relationship changes: the increase in VEGF-A coexists with lower eNOS activity, and there is VEGF-A and NO decoupling50. Along the lines of this theory, a study of diabetic mice with no eNOS reported an increase in VEGF-A expression and severe DN50. We showed that VEGF overexpression in podocytes, associated with an absence of eNOS, induced indistinguishable changes in advanced DN35. In the absence of diabetes, these transgenic mice developed proteinura, kidney failure and nodular glomerulosclerosis35. This evidence suggests that alterations in glomerular VEGF-A/NO-eNOS ratio are critical and very dangerous, highlighting these events and their relationship with VEGF-A as treatment targets at the glomerular level. Endothelial NO deficiency secondary to reduced eNOS activity may also associate insulin resistance mechanisms with endothelial dysfunction47,48. Endothelial cells express insulin receptors. By means of eNOS activation, these receptors control vascular tone by inducing vasodilation. For example, in patients with diabetes there are alterations in eNOS activation, establishing a relationship between NO and endothelial insulin resistance47-49. These findings suggest that VEGF-A and the glomerular NO/eNOS ratio may be implied in the insulin resistance status associated with prediabetes, diabetes and CKD.Conclusions Population studies reveal an increasing prevalence of type 2 diabetes worldwide, which suggests that DN will become an even more serious problem. It is imperative to look for alternatives for the diagnosis, prevention and treatment of DN. Going further in the study of molecular pathways with therapeutic potential, such as angiogenic factors, the glomerular VEGF resistance status, insulin resistance in podocytes, the VEGFR2/nephrin ratio, VEGF/insulin receptors /nephrin ratio, and the VEGF/NO-eNOS ratio, may provide solutions to the urgent problem of DN in the world.Key concepts 1. Diabetes mellitus and CKD prevalence have increased in recent decades. The most frequent isolated cause of CKD is DN. Factors related to DN development are: age over 65, uncontrolled hyperglycaemia, hypertension blood pressure, dyslipidaemia, male gender, smoking habit, family history, and Hispanic or Afro-American origin. 2. Glucose directly and indirectly stimulates VEGF-A cell expression. In DN, there is a systemic and glomerular increase in VEGF-A, but glomerular VEGF-A and the glomerular VEGF-A/NO-eNOS ratio are key factors in DN pathophysiogenesis. 3. Endothelial cells and podocytes express insulin receptors. Nephrin is essential for the action of the insulin receptor in podocytes; its activation is related to VEGF-A. VEGFR2 and nephrin interact in podocytes. Insulin receptors, nephrin and VEGF-A receptors may be mechanistically related to DN and insulin resistance. 4. In DN, VEGF overexpression in podocytes may be stimulated in an autocrine and paracrine way by a “VEGF-resistance” status, in which PKC and ROS would be involved. VEGF-A connections to oxidative stress at the glomerular level may represent pathways with a therapeutic potential for DN. 5. Angiogenic factors, such as VEGF-A and angiopoietins, VEGF resistance status, insulin resistance in podocytes, VEGFR2/nephrin ratio, VEGF-A/insulin receptors/nephrin ratio, and VEGF/NO-eNOS ratio, represent glomerular pathways that have a crucial significance and may be potential treatment targets for DN.Acknowledgements We would like to thank Maitén Fernández Verón, Facultad de Arquitectura, Diseño y Urbanismo [School of Architecture, Desig n and Urbanism], Universidad de Buenos Aires [University of Buenos Aires], Argentina for collaborating in the design of the Figures. We would also like to thank Eco. Patricio Álvarez, UNEMI (Universidad Estatal de Milagro [State University of Milagro]) for helping in the publication processes and Gonzalo Fernández Verón for the language review.<hr></hr> Sent for Review: 05 Nov 2014 Accepted on: 03 Dec 2014<a href="http://dx.doi.org/10.3265/Nefrologia.pre2014.Dec.12808" class="elsevierStyleCrossRefs">http://dx.doi.org/10.3265/Nefrologia.pre2014.Dec.12808</a> * Corresponding author. Delma Veron, School of Health Sciences, Universidad Estatal de Milagro, Ciudadela Universitaria, UNEMI, Kilómetro 1 ½ Vía KM 26., 091050, Milagro, Guayas, Ecuador. Tel.: (593) 46038456 E-mail: delveron@gmail.com; <a href="mailto:proyectond@hotmail.com" class="elsevierStyleCrossRefs">proyectond@hotmail.com</a>" "pdfFichero" => "498v35n02a90411910pdf001.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec503476" "palabras" => array:19 [ 0 => "Nefropatía diabética" 1 => "VEGF-A" 2 => "VEGF" 3 => "Podocito" 4 => "Endotelio" 5 => "Barrera de filtración glomerular" 6 => "VEGFR2" 7 => "Receptores de VEGF" 8 => "Óxido nítrico" 9 => "Receptor de insulina" 10 => "Angiopoietina" 11 => "ROS" 12 => "Riñón" 13 => "Diabetes mellitus" 14 => "Proteinuria" 15 => "Sudamérica" 16 => "Angiogénesis" 17 => "Enfermedad renal crónica" 18 => "Insulinorresistencia" ] ] ] "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec503475" "palabras" => array:15 [ 0 => "Diabetic nephropathy, VEGF-A, VEGF" 1 => "Podocyte" 2 => "Endothelium" 3 => "Glomerular filtration barrier" 4 => "VEGFR2, VEGF receptors" 5 => "Nitric oxide" 6 => "Insulin receptor" 7 => "Angiopoietin" 8 => "ROS" 9 => "Kidney" 10 => "Diabetes mellitus proteinuria" 11 => "South America" 12 => "Angiogenesis" 13 => "Chronic kidney disease" 14 => "Insulin resistance" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => " La prevalencia de diabetes mellitus aumentó en el último siglo y se estima que el 45% de los pacientes, no estarían diagnosticados. En Sudamérica la prevalencia de diabetes y de enfermedad renal crónica (ERC) incrementó, existiendo gran disparidad entre los países respecto al acceso a diálisis. En Ecuador es una de las principales causas de mortalidad, principalmente en las provincias ubicadas en la costa del océano Pacífico. La mayor causa aislada de ingreso a diálisis es la nefropatía diabética (ND). Aun utilizando las mejores opciones terapéuticas para la ND, el riesgo residual de proteinuria y de ERC terminal permanece elevado. En esta revisión describimos la importancia del problema en el mundo y en nuestra región. Analizamos estudios moleculares y celulares relevantes que indican la crucial importancia de eventos glomerulares en el desarrollo y en la evolución de la ND y en la insulinorresistencia. Incluimos conceptos anatómicos, fisiopatológicos y clínicos básicos, desarrollando especial énfasis en el rol de factores angiogénicos como el factor de crecimiento vascular endotelial (VEGF-A) y su relación con el receptor de insulina, la sintasa endotelial de óxido nítrico-óxido nítrico (eNOS) y las angiopoietinas. En el transcurso del texto proponemos diversas vías, que a nuestro entender tienen potencial terapéutico. Profundizar en el estudio del VEGF-A y las angiopoietinas, el estado de VEGF resistencia glomerular, la relación del receptor 2 de VEGF/ nefrina, VEGF/receptores de insulina/nefrina, la relación VEGF/eNOS-ON a nivel glomerular podría aportar soluciones al acuciante problema de la ND en el mundo y generar nuevas alternativas de tratamiento." ] "en" => array:1 [ "resumen" => " The prevalence of diabetes mellitus increased in the last century, and it is estimated that 45% of patients have not yet been diagnosed. In South America, diabetes and chronic kidney disease (CKD) prevalence increased, and there is great disparity regarding access to dialysis among these countries. In Ecuador, it is one of the major causes of mortality, mainly in provinces located on the Pacific coast. The main cause of admission to dialysis is diabetic nephropathy (DN). Even when the best therapeutic options for DN are used, the residual risk of proteinuria and end-stage CKD continues to be high. In this review, we describe the magnitude of the issue both worldwide and locally. We analysed relevant molecular and cellular studies, which indicate the crucial significance of glomerular events in DN development and progress and in insulin resistance. We included basic anatomical, pathophysiological and clinical concepts, with special emphasis on the role played by angiogenic factors, such as vascular endothelial growth factor (VEGF-A) and its relationship with the insulin receptor, endothelial nitric oxide synthase (eNOS) and angiopoietins. Throughout the text, we suggest several pathways, which, in our opinion, have therapeutic potential. Going further in the study of VEGF-A and angiopoietins, glomerular VEGF resistance status, the VEGF receptor 2/nephrin ratio, VEGF/receptors of insulin/nephrin ratio, the VEGF/NO-eNOS ratio at glomerular level may provide solutions to the urgent issue of DN worldwide and lead to new treatment alternatives." ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "498v35n02-90411910fig1.jpg" "Alto" => 750 "Ancho" => 908 "Tamanyo" => 74235 ] ] "descripcion" => array:1 [ "en" => "– In Ecuador, mortality caused by diabetes mellitus was higher in the provinces of Guayas, Los Ríos and Manabí, located on the Pacific coast. Map shows the mortality rate due to diabetes mellitus (deaths/100,000 individuals per year, INEC [Instituto Nacional de Estadísticas y Censos - National Institute of Statistics and Census of Ecuador] 2011). This figure is part of a figure originally published by Neira-Mosquera et al.6, with minor modifications (authorised reproduction)." ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "498v35n02-90411910fig2.jpg" "Alto" => 1154 "Ancho" => 2145 "Tamanyo" => 310819 ] ] "descripcion" => array:1 [ "en" => "– Schematic representation of the glomerulus, the glomerular filtration barrier (GFB) composed of podocytes (P), the glomerular basal membrane (GBM), and the endothelium. Plasma ultrafiltration passes through the GFB (black arrow) to reach the urinary space (US). Podocytes (green) make contact with several glomerular capillaries (represented as red circles) and the intraglomerular mesangium (M). The GBM (black line) wraps the capillaries and surrounds the mesangium. The glomerular endothelium is represented by a discontinuous light-blue line, located between the capillary lumen (CL) and the GBM, the vascular pole in the lower part of the glomerulus, the tubular pole in the upper part. B: Ultrastructure of the GFB observed with an electronic microscope: podocytes, GBM, slit diaphragm (SD) and fenestrated endothelium. Plasma ultrafiltration passes through the GFB (yellow arrow) from the capillary lumen (CL) towards the urinary space (US)." ] ] 2 => array:8 [ "identificador" => "tbl1" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "498v35n02-90411910fig3.jpg" "imagenAlto" => 566 "imagenAncho" => 1041 "imagenTamanyo" => 101378 ] ] ] ] ] "descripcion" => array:1 [ "en" => "– Glomerular pathways with therapeutic potential for DN" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:50 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Global estimates of diabetes prevalence for 2013 and projections for 2035. 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Aspectos celulares y moleculares de la nefropatía diabética, rol del VEGF-A

Katherine Carranzaa, Dolores Veronb, Alicia Cercadoc, Noemi Bautistac, Wilson Pozod, Alda Tufroe, Delma Veronc

a School of Medicine, School of Medical Sciences, Universidad de Guayaquil [University of Guayaquil]. Guayaquil, Guayas (Ecuador)

b School of Social Work, School of Law and Social Sciences, Universidad Nacional de Córdoba [National University of Córdoba], Córdoba, Córdoba (Argentina)

c School of Health Sciences, Universidad Estatal de Milagro [State University of Milagro], Milagro, Guayas (Ecuador)

d School of Natural Sciences, Universidad de Guayaquil, Guayaquil. Guayas (Ecuador)

e Department of Paediatrics, School of Medicine, Yale University, New Haven, Connecticut (USA)

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          "en" => "– In Ecuador&#44; mortality caused by diabetes mellitus was higher in the provinces of Guayas&#44; Los R&#237;os and Manab&#237;&#44; located on the Pacific coast&#46; Map shows the mortality rate due to diabetes mellitus &#40;deaths&#47;100&#44;000 individuals per year&#44; INEC &#91;Instituto Nacional de Estad&#237;sticas y Censos - National Institute of Statistics and Census of Ecuador&#93; 2011&#41;&#46; This figure is part of a figure originally published by Neira-Mosquera et al&#46;6&#44; with minor modifications &#40;authorised reproduction&#41;&#46;"
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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Issue relevance </span></p><p class="elsevierStylePara"> The prevalence of diabetes mellitus has increased worldwide since the last century<span class="elsevierStyleSup">1</span>&#46; In adults aged between 20 and 79 years of age&#44; its prevalence reaches 8&#37;<span class="elsevierStyleSup">1</span>&#46; Diabetes spreads through rich and poor countries&#44; but it is prevalent in vulnerable groups and lower-income regions of the world&#46; Territories showing the highest numbers of affected individuals are&#58; China&#44; India&#44; the United States&#44; Brazil and Russia<span class="elsevierStyleSup">1</span>&#46; This situation is associated with greater urbanisation&#44; low socioeconomic level&#44; inequality&#44; increased life expectancy and population density&#44; ethnic factors&#44; nutrition&#44; physical inactivity&#44; and being overweight<span class="elsevierStyleSup">1&#44;2</span>&#46; In Spain&#44; a diabetes prevalence rate of 13&#46;8&#37; was reported&#44; while 6&#46;8&#37; had not yet been diagnosed<span class="elsevierStyleSup">3</span>&#46; Recent estimates suggest that worldwide prevalence will have doubled by 2035&#44; while in our region&#44; South America and Central America&#44; it will have increased to 9&#46;8&#37;<span class="elsevierStyleSup">1&#44;2</span>&#46; In addition&#44; 45&#46;5&#37; of individuals with diabetes will not be diagnosed with the disease<span class="elsevierStyleSup">1&#44;2</span>&#46;</p><p class="elsevierStylePara"> In the urban population located on the coasts of our region&#44; diabetes prevalence is higher than in the mountains or the jungle&#44; and the same happens with people who move from the rural to the urban environment<span class="elsevierStyleSup">1-2</span>&#46; Moreover&#44; native populations are particularly vulnerable due to the change in lifestyle&#44; marginalisation and lower exposure to health care systems<span class="elsevierStyleSup">2</span>&#46; In Ecuador&#44; the prevalence of diabetes is 6&#37;&#44; and in 2010 it was the second cause of mortality<span class="elsevierStyleSup">2&#44;4&#44;5</span>&#46; In the provinces of Guayas&#44; Los R&#237;os and Manab&#237;&#44; located on the Pacific coast&#44; the mortality rate due to diabetes and industrialised food consumption is higher&#59; meanwhile&#44; in the Amazon&#44; natural food-based nutrition predominates and the rate is lower<span class="elsevierStyleSup">6</span> &#40;Figure 1&#41;&#46;</p><p class="elsevierStylePara"><img alt="Figure 1 – In Ecuador&#44; mortality caused by diabetes mellitus was higher in the provinces of Guayas&#44; Los R&#237;os and Manab&#237;&#44; located on the Pacific coast&#46; Map shows the mortality rate due to diabetes mellitus &#40;deaths&#47;100&#44;000 individuals per year&#44; INEC &#91;Instituto Nacional de Estad&#237;sticas y Censos - National Institute of Statistics and Census of Ecuador&#93; 2011&#41;&#46; This figure is part of a figure originally published by Neira-Mosquera et al&#46;6&#44; with minor modifications &#40;authorised reproduction&#41;&#46;" src="498v35n02-90411910fig1.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figure 1 &#8211; In Ecuador&#44; mortality caused by diabetes mellitus was higher in the provinces of Guayas&#44; Los R&#237;os and Manab&#237;&#44; located on the Pacific coast&#46; Map shows the mortality rate due to diabetes mellitus &#40;deaths&#47;100&#44;000 individuals per year&#44; INEC &#91;Instituto Nacional de Estad&#237;sticas y Censos - National Institute of Statistics and Census of Ecuador&#93; 2011&#41;&#46; This figure is part of a figure originally published by Neira-Mosquera et al&#46;6&#44; with minor modifications &#40;authorised reproduction&#41;&#46;</span></p><p class="elsevierStylePara"> Kidney disease caused by diabetes is called diabetic nephropathy &#40;DN&#41;&#46; About 30&#37; of patients with diabetes develop DN<span class="elsevierStyleSup">7&#44;8</span>&#46; Such disease is the main cause of chronic kidney disease &#40;CKD&#41; and of admission to dialysis<span class="elsevierStyleSup">7-11</span>&#46; The increase in adult diabetes has been recorded in the last few decades&#44; and CKD affects 10&#37; to 16&#37; of adults&#44; which constitutes a serious worldwide problem<span class="elsevierStyleSup">7-11</span>&#46; In South America&#44; the prevalence of diabetes and end-stage CKD &#40;ECKD&#41; has increased in recent decades&#44; and access to dialysis varies greatly among these countries<span class="elsevierStyleSup">9-11</span>&#46; In Ecuador&#44; the prevalence of patients who received renal function replacement therapy in 2010 was 406 individuals per one million inhabitants<span class="elsevierStyleSup">11</span>&#46; On the other hand&#44; the renin-angiotensin-aldosterone system &#40;RAAS&#41; inhibitors constitute the best therapeutic option for DN&#44; but the residual risk of ECKD continues to be high and the association of these drugs was related to hyperpotassemia and acute kidney failure &#40;AKF&#41;<span class="elsevierStyleSup">12-13</span>&#46; The search for new therapeutic alternatives is necessary&#46;</p><p class="elsevierStylePara"> Population studies raise awareness of the problem&#44; while the knowledge generated in research laboratories expand our understanding of the biological events that occur in individuals&#46; In this review&#44; we will include anatomical and patho-physiological concepts that reveal the crucial importance of events occurring at the glomerular level&#46; In addition&#44; we will analyse the role played by the vascular endothelial growth factor &#40;VEGF-A&#41; and its relationships with nitric oxide &#40;NO&#41;&#44; the insulin receptor and angiopoietins&#46; Finally&#44; we will consider basic aspects and the analyses of recently published molecular and cellular studies&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Anatomical and pathophysiological aspects of DN </span></p><p class="elsevierStylePara"> Diabetes involves functional and structural kidney alterations that induce proteinuria at variable magnitudes&#44; ranging from micrograms to several grams per day<span class="elsevierStyleSup">7&#44;8&#44;13</span>&#46; The risk of developing ECKD is related to albumin urinary excretion&#44; and early detection of RAAS inhibitors is important due to the beneficial renal and systemic effects<span class="elsevierStyleSup">7&#44;8&#44;13</span>&#46; DN is accompanied by persistent albumin urinary excretion or microalbuminuria&#44; which is defined as the loss of urinary albumin ranging from 20 to 199 &#181;g&#47;min or 30 to 299 mg&#47;d on two different occasions and when the albumin&#47;creatinine ratio is 30-299 mg&#47;g in an isolated urine sample<span class="elsevierStyleSup">7&#44;8</span>&#46; In type 1 diabetes&#44; albumin urinary excretion should be quantified on an annual basis&#44; from the fifth year following diagnosis onwards&#59; in type 2 diabetes&#44; given the difficulty to accurately state its onset&#44; measurement is preferable from the moment the disease is diagnosed<span class="elsevierStyleSup">7&#44;8</span>&#46; In one study&#44; the prevalence of microalbuminuria in patients with type 2 diabetes was 24&#46;9&#37; after a ten-year follow-up<span class="elsevierStyleSup">14</span>&#44; but 30&#37; of patients with type 2 diabetes and no microalbuminuria developed DN&#46; It is also important to quantify glomerular filtration &#40;GF&#41;&#44; since some patients only show renal function impairment with no signs of proteinur ia<span class="elsevierStyleSup">7&#44;8</span>&#46; Considering that 85&#37; of the patients with diabetes have type 2 diabetes&#44; better biomarkers are required<span class="elsevierStyleSup">7&#44;8&#44;13&#44;14</span>&#46;</p><p class="elsevierStylePara"> Risk factors contributing to the development of DN are hyperglycaemia&#44; hypertension &#40;HTN&#41;&#44; dyslipidaemia&#44; age over 65 years&#44; male gender&#44; smoking habit&#44; family history and Hispanic or Afro-American origin<span class="elsevierStyleSup">7&#44;8</span>&#46; Familial clustering was reported in populations with different ancestors&#44; especially in Pima Indians and Afro-Americans<span class="elsevierStyleSup">16</span>&#46; Mooyaart et al&#46; found 24 genetic variations associated with DN<span class="elsevierStyleSup">17</span>&#46; Epigenetic mechanisms were also implied<span class="elsevierStyleSup">8&#44;18</span>&#46; For example&#44; chronic hyperglycaemia&#44; without altering the nucleotide sequence&#44; may modify DNA or methylate histones associated with DNA<span class="elsevierStyleSup">18</span>&#46; However&#44; the significance of these findings on the development of DN has not been determined yet&#46;</p><p class="elsevierStylePara"> Many factors were implied in DN pathophysiology&#44; such as&#58; glucose&#44; glucose receptors&#44; VEGF-A&#44; NO&#44; reactive oxygen species &#40;ROS&#41;&#44; transforming growth factor beta &#40;TGF-Beta&#41;&#44; RAAS&#44; kinin-kallikrein system&#44; mammalian target of rapamycin&#44; inflammation&#44; tumour necrosis factor alpha&#44; adiponectin&#44; advanced glycation end products and receptors thereof&#44; mitochondr ial oxidat ive stress and micro-RNA<span class="elsevierStyleSup">7&#44;8&#44;15&#44;19&#44;20-22</span>&#46;</p><p class="elsevierStylePara"> From the pathologic point of view&#44; type 1 and type 2 diabetes induce common kidney lesions&#46; These lesions were characterised in type 1 diabetes<span class="elsevierStyleSup">7&#44;8&#44;15&#44;23-26</span>&#46; In type 2 diabetes&#44; the kidney histology and course have special features&#44; associated with comorbidities such as HTN&#44; vascular diseases&#44; ageing and obesity<span class="elsevierStyleSup">7&#44;8&#44;23-24</span>&#46; Five years after diabetes diagnosis&#44; there is hyperfiltration&#44; microalbuminuria&#44; glomerulomegaly&#44; glomerular basal membrane &#40;GBM&#41; thickening and alteration of podocytes<span class="elsevierStyleSup">26</span>&#46; Subsequently&#44; the extracellular matrix &#40;ECM&#41; is deposited in the mesangium&#46; Approximately ten years later&#44; proteinuria and HTN are evident&#44; and GF becomes progressively impaired<span class="elsevierStyleSup">7&#44;23&#44;24&#44;26</span>&#46; Within a period of 20 to 25 years&#44; sclerosis is advanced&#44; there is tubulointerstitial fibrosis and CKD progresses to end-stage phases<span class="elsevierStyleSup">7&#44;24-26</span>&#46;</p><p class="elsevierStylePara"> Meanwhile&#44; the glomeruli&#44; tubules&#44; interstitium and renal arteries are modified by the diabetic environment&#46; Glomerular changes involve the glomerular filtration barrier &#40;GFB&#41;&#44; ECM&#44; and the main cells composing it &#40;podocytes&#44; endothelial cells and mesangial cells&#41;<span class="elsevierStyleSup">7&#44;16&#44;19-21-25</span>&#46; In addition&#44; it prevents the abnormal passage of plasma protein based on size and load&#44; and its alteration was associated with proteinuria<span class="elsevierStyleSup">7&#44;15&#44;19&#44;20&#44;25</span>&#46; The GFB is composed of podocytes&#44; GBM&#44; and the endothelium &#40;Figure 2&#41;&#46; Podocytes are markedly differentiated epithelial cells&#44; with a large cell body&#44; and primary and secondary extensions connected by slit diaphragms &#40;SD&#41;<span class="elsevierStyleSup">15&#44;19&#44;20</span>&#46; The SD is permeable to water and small solutes&#44; but it is selective to large molecule passage&#44; which is a key factor in GFB permeability<span class="elsevierStyleSup">25</span>&#46; Moreover&#44; it is composed of a protein complex&#44; where nephrin plays an important role<span class="elsevierStyleSup">7&#44;15&#44;19&#44;20</span>&#46; On the apical side&#44; podocytes float within the urinary space&#44; while on the baso-lateral side&#44; they make contact with the GBM&#46; Podocyte cytoskeleton proteins are related to GBM proteins through integrins and dystroglycans<span class="elsevierStyleSup">15&#44;20&#44;25</span>&#46; The GBM is mainly composed of proteins&#44; such as collagen IV and laminins<span class="elsevierStyleSup">15&#44;25</span>&#46; The fenestrated endothelium&#44; covered by glycocalyx&#44; is the inner most layer of the GFB<span class="elsevierStyleSup">7&#44;15&#44;21&#44;25</span>&#46; Diabetes alters the three layers that make up the GFB&#46; Among the early changes&#44; neoangio-genesis in the glomerular vascular pole and loss of endothelial fenestrations have been described<span class="elsevierStyleSup">7&#44;16&#44;22&#44;23</span>&#46; The GBM shows an increased thickness due to protein exchange alterations<span class="elsevierStyleSup">7&#44;15&#44;19&#44;20&#44;25</span>&#46; In podocytes&#44; f lattening&#44; hypertrophy&#44; detachment and apoptosis are observed in the early stages&#44; while later podocytopenia is observed<span class="elsevierStyleSup">7&#44;15&#44;19&#44;20</span>&#46;</p><p class="elsevierStylePara"><img alt="Figure 2 – Schematic representation of the glomerulus&#44; the glomerular filtration barrier &#40;GFB&#41; composed of podocytes&#160;&#40;P&#41;&#44;&#160;the&#160;glomerular basal membrane &#40;GBM&#41;&#44; and the endothelium&#46; Plasma ultrafiltration passes through the GFB &#40;black arrow&#41; to reach the urinary space &#40;US&#41;&#46; Podocytes &#40;green&#41; make contact with several glomerular capillaries &#40;represented as red circles&#41; and the intraglomerular mesangium &#40;M&#41;&#46; The GBM &#40;black line&#41; wraps the capillaries and surrounds the mesangium&#46; The glomerular endothelium is represented by a discontinuous light-blue line&#44; located between the capillary lumen &#40;CL&#41; and the GBM&#44; the vascular pole in the lower part of the glomerulus&#44; the tubular pole in the upper part&#46; B&#58; Ultrastructure of the GFB observed with an electronic microscope&#58; podocytes&#44; GBM&#44; slit diaphragm &#40;SD&#41; and fenestrated endothelium&#46; Plasma ultrafiltration passes through the GFB &#40;yellow arrow&#41; from the capillary lumen &#40;CL&#41; towards the urinary space &#40;US&#41;&#46;" src="498v35n02-90411910fig2.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figure 2 &#8211; Schematic representation of the glomerulus&#44; the glomerular filtration barrier &#40;GFB&#41; composed of podocytes&#160;&#40;P&#41;&#44;&#160;the&#160;glomerular basal membrane &#40;GBM&#41;&#44; and the endothelium&#46; Plasma ultrafiltration passes through the GFB &#40;black arrow&#41; to reach the urinary space &#40;US&#41;&#46; Podocytes &#40;green&#41; make contact with several glomerular capillaries &#40;represented as red circles&#41; and the intraglomerular mesangium &#40;M&#41;&#46; The GBM &#40;black line&#41; wraps the capillaries and surrounds the mesangium&#46; The glomerular endothelium is represented by a discontinuous light-blue line&#44; located between the capillary lumen &#40;CL&#41; and the GBM&#44; the vascular pole in the lower part of the glomerulus&#44; the tubular pole in the upper part&#46; B&#58; Ultrastructure of the GFB observed with an electronic microscope&#58; podocytes&#44; GBM&#44; slit diaphragm &#40;SD&#41; and fenestrated endothelium&#46; Plasma ultrafiltration passes through the GFB &#40;yellow arrow&#41; from the capillary lumen &#40;CL&#41; towards the urinary space &#40;US&#41;&#46;</span></p><p class="elsevierStylePara"> Recently published articles that relate VEGF-A to glomerular proteins involved in human and experimental DN pathophysiogenesis are analysed below&#46; Throughout the text&#44; we will suggest several pathways which may be used to generate new therapeutic tools &#40;Table 1&#41;&#46;</p><p class="elsevierStylePara"><img alt="Table 1 – Glomerular pathways with therapeutic potential for DN" src="498v35n02-90411910fig3.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">The role of VEGF-A in DN </span></p><p class="elsevierStylePara"> VEGF-A is a potent angiogenic factor related to normal and pathological angiogenesis&#46; It promotes the proliferation&#44; differentiation and migration of endothelial cells&#59; it induces vasodilation and increases vascular permeability<span class="elsevierStyleSup">15&#44;19&#44;20&#44;27</span>&#46; It plays an important role in kidney development&#59; in the adult kidney&#44; it is secreted by podocytes and is essential for the maintenance of the GFB<span class="elsevierStyleSup">15</span>&#46; It acts through tyrosine-kinase receptors&#44; which are known as VEGF receptor 1 and 2 &#40;VEGFR1 and 2&#41;<span class="elsevierStyleSup">15&#44;27</span>&#46; VEGFR2 is expressed in endothelial cells and podocytes&#59; it is related to the most important signals of VEGF-A<span class="elsevierStyleSup">15&#44;27</span>&#46; Two co-receptors called neuropilins 1 and 2 amplify the VEGFR2 signal<span class="elsevierStyleSup">15&#46;27</span>&#46;</p><p class="elsevierStylePara"> There is evidence that glucose directly and indirectly stimulates VEGF-A expression in podocytes through angiotensin II and TGF-Beta<span class="elsevierStyleSup">15&#44;19&#44;20</span>&#46; Glucose plays a very important role in DN pathophysiogenesis&#46; Glycaemic control reduces DN progression and induces reversion of proteinuria and advanced histological lesions<span class="elsevierStyleSup">28-32</span>&#46; In a 30-year follow-up study&#44; proteinuria&#44; GF and HTN showed an improvement in patients with type 1 diabetes when there was better glycaemic control<span class="elsevierStyleSup">28</span>&#46; With a higher control of hyperglycaemia&#44; GBM has shown less thickening<span class="elsevierStyleSup">29</span>&#46; Histological changes of advanced DN reverted 10 years after pancreas transplantation<span class="elsevierStyleSup">30</span>&#46; Haraguchi et al&#46; were able to revert nephrotic-range proteinuria and histological lesions compatible with advanced DN after five years of intensive treatment of hyperglycaemia<span class="elsevierStyleSup">31</span>&#46; Treatment with bariatric surgeries administered to patients with type 2 diabetes and obesity improved GF and proteinuria&#44; which was related to weight loss and decreased hyperglycaemia<span class="elsevierStyleSup">32</span>&#46;</p><p class="elsevierStylePara"> Hyperglycaemia increases renin and angiotensinogen expression in mesangial cells<span class="elsevierStyleSup">20</span>&#46; Mesangial cells and podocytes synthesise angiotensin II and express angiotensin receptors<span class="elsevierStyleSup">19&#44;20</span>&#46; The increase in angiotensin II stimulates the expression of TGF-Beta&#44; VEGF-A&#44; connective tissue growth factor &#40;CTGF&#41;&#44; interleukin 6 and chemoattractant protein for monocytes-1 inducing expansion of the ECM and podocyte apoptosis<span class="elsevierStyleSup">7&#44;15&#44;19&#44;20</span>&#46;</p><p class="elsevierStylePara"> In addition&#44; glucose increases TGF-Beta expression in mesangial cells and podocytes<span class="elsevierStyleSup">19</span>&#46; Active TGF-Beta induces GBM thickening and glomerulosclerosis through the VEGF and CTGF&#59; the increase in VEGF-A inhibits TGF-Beta expression&#44; in a negative feedback mechanism<span class="elsevierStyleSup">15&#44;19&#44;20</span>&#46; In contrast&#44; the increase in VEGF-A in diabetes is associated with elevated TGF-Beta and CTGF&#44; proliferation and build-up of proteins in the glomerular ECM<span class="elsevierStyleSup">15&#44;19&#44;20</span>&#46; TGF-Beta has been related to the proliferation of mesangial cells&#44; diffuse nodular glomerulo-sclerosis and also fibrosis<span class="elsevierStyleSup">15&#44;19&#44;20</span>&#46; In transgenic mice with no TGF-Beta type 2 receptor&#44; the administration of anti-TGF-Beta antibodies prevented mesangial build-up and kidney function impairment<span class="elsevierStyleSup">19&#44;20</span>&#46; These antibodies represent a therapeutic hope for DN&#44; but they are not available for human use yet<span class="elsevierStyleSup">19</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Glomerular VEGF-A modifications in DN </span></p><p class="elsevierStylePara"> Starting from early DN stages&#44; systemic and renal VEGF-A are elevated in humans and mice&#44; and they have also been associated with neoangigenesis<span class="elsevierStyleSup">15&#44;21&#44;22</span>&#46; RAAS&#44; VEGF-A and nephrinuria were seen to be involved in this process<span class="elsevierStyleSup">15&#44;19&#44;20&#44;22&#44;33-38</span>&#44; while cultured podocytes and endothelial cells increased VEGF-A and VEGFR2 expression in response to the increase in glucose<span class="elsevierStyleSup">39-41</span>&#46; We showed that glomerular VEGF is a key factor for DN development and progress<span class="elsevierStyleSup">33-34</span>&#46; Normoglycaemic mice with VEGF overexpression in podocytes developed glomerulomegaly&#44; hyperfiltration&#44; GBM thickening and podocyte lesion&#44; which are changes similar to early DN<span class="elsevierStyleSup">33</span>&#46; In these transgenic mice&#44; diabetes caused massive proteinuria&#44; advanced nodular glomerulosclerosis and less nephrin expression<span class="elsevierStyleSup">34</span>&#46; Diabetic mice with no VEGF overexpression only showed mild diffuse glomerulosclerosis<span class="elsevierStyleSup">34</span>&#46; These experiments show that the increase in glomerular VEGF&#44; irrespective of the diabetic environment&#44; generates identical changes in early DN and that increasing glomerular VEGF speeds up DN progress to more advanced stages&#46; In the absence of diabetes&#44; the urinary VEGF-A was reported to be a good marker of VEGF glomerular expression and it correlated with proteinuria<span class="elsevierStyleSup">33</span>&#46; Contrarily&#44; in the case of diabetes&#44; VEGF-A has not been observed to be a good marker of glomerular expression or DN severity&#46; Urine and systemic VEGF-A levels were high in diabetic mice with and without glomerular VEGF overexpression<span class="elsevierStyleSup">34</span>&#46; Probably&#44; within the diabetes context&#44; urinary excretion of VEGF-A reflects systemic levels&#44; while hiding VEGF glomerular changes<span class="elsevierStyleSup">34</span>&#46; In short&#44; these experiments suggest that glomerular VEGF-A is a determining factor in DN&#44; that VEGF overexpression in podocytes is dangerous&#44; and that glucose directly and indirectly stimulates the VEGF-A signalling cascade in podocytes&#46; In diabetes&#44; urinary and systemic VEGF-A did not correlate with either glomerular VEGF expression or with the severity of glomerular lesions&#44; which brings into question the use of VEGF-A as a DN biomarker&#46;</p><p class="elsevierStylePara"> Glomerular VEGF-A reduction was shown to generate GFB lesions&#44; proteinuria and kidney failure in animals and humans<span class="elsevierStyleSup">42&#44;43</span>&#46; Transgenic mice with silencing of VEGF-A in podocytes showed AKF&#44; alteration of the three GFB layers and reduced integrin expression<span class="elsevierStyleSup">43</span>&#46; Some patients treated with anti-VEGF-A antibodies showed proteinuria&#44; endothelial lesions and thrombotic microangiopathy<span class="elsevierStyleSup">42</span>&#46; This evidence suggests that VEGF-A released by podocytes is important for the maintenance of the function and the glomerular structure in the adult kidney&#46; Whether glomerular VEGF-A expression control improves DN has not yet been determined&#44; but there is evidence that shows contradictory results&#46; Administration of anti-VEGF antibodies improved DN in rodents<span class="elsevierStyleSup">44</span>&#46; In experiments conducted in mice&#44; endostatin and tumstatin prevented the development of DN due to a decrease in VEGF-A and angiopoietin 2<span class="elsevierStyleSup">36</span>&#46; In contrast&#44; diabetic mice with gene deletion of VEGF-A in podocytes showed proteinuria and severe diffuse glomerulosclerosis associated with endothelial injury and apoptosis<span class="elsevierStyleSup">42</span>&#46;</p><p class="elsevierStylePara"> The evidence described herein suggests that close monitoring of glomerular VEGF-A levels in diabetes is required in order to avoid adding new lesions or worsening DN&#46; Monitoring glomerular VEGF-A expression within very close margins may have a therapeutic potential&#44; but the optimal concentrations and the right moment to perform such manipulation have not yet been defined&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">VEGF-A relationships with insulin receptors&#44; nephrin and ROS in DN </span></p><p class="elsevierStylePara"> In DN&#44; glomeruli with different lesion degrees coexist&#59; VEGF-A expression and its signalling cascade have been related to glomerular changes<span class="elsevierStyleSup">37</span>&#46; In biopsies of patients with DN&#44; there has been evidence of a higher VEGF expression in the glomeruli with lesions due to diabetes than in intact glomeruli<span class="elsevierStyleSup">37</span>&#46; However&#44; VEGF-bound receptor expression was seen to be elevated in glomeruli with mild lesions and decreased in glomeruli with moderate or severe compromise<span class="elsevierStyleSup">37</span>&#46; A similar behaviour was observed with phosphorylation of serine&#47;threonine protein kinase&#44; a protein located in the VEGF signalling cascade&#44; which suggested that other factors would modulate VEGF&#47;VEGFR activity<span class="elsevierStyleSup">37</span>&#46;</p><p class="elsevierStylePara"> Podocytes express insulin receptors&#44; whose activity depends on nephrin expression<span class="elsevierStyleSup">45&#44;46</span>&#46; Insulin receptors are located in the SD&#44; where podocytes express nephrin and VEGFR2<span class="elsevierStyleSup">33&#44;46</span>&#46; We have characterised the existing interaction between nephrin and VEGFR2<span class="elsevierStyleSup">16</span>&#46; VEGF overexpression in podocytes was found to decrease nephrin expression and phosphor ylation<span class="elsevierStyleSup">16&#44;33</span>&#46; Hale et al&#46; reported that insulin increases VEGF-A production in podocytes&#44; both in humans and mice<span class="elsevierStyleSup">45</span>&#46; In transgenic mice&#44; this VEGF-A increase was disrupted by insulin resistance&#44; anticipating the development of podocyte lesions secondary to insulin resistance<span class="elsevierStyleSup">45</span>&#46; In patients with insulin resistance caused by diabetes and by other diseases&#44; kidney alterations&#44; such as hyperfiltration&#44; proteinuria&#44; modifications in FGB and mesangium were described<span class="elsevierStyleSup">47&#44;48</span>&#46; Jointly&#44; these findings suggest that VEGF&#44; nephrin and insulin receptor may be related to DN and insulin resistance&#44; thus constituting glomerular pathways susceptible to being modified&#46;</p><p class="elsevierStylePara"> Furthermore&#44; oxidative stress secondary to hyperglycaemia may modify glycocalyx&#44; increase ROS and advanced glycation end products&#44; and alter the endothelium&#46; In addition&#44; protein kinase C &#40;PKC&#41; glomerular activation was associated with mesangial expansion&#44; GBM thickening&#44; endothelial dysfunction&#44; cytokine and TGF-Beta activation<span class="elsevierStyleSup">7&#44;15&#44;21&#44;40&#44;41</span>&#46; Mima et al&#46; described that hyperglycaemia alters nephrin phosphorylation in diabetic rats and cultured podocytes exposed to high concentrations of glucose<span class="elsevierStyleSup">49</span>&#46; Nephrin phosphorylation interruption was attributed to a &#8220;glomerular VEGF resistance&#8221; status related to PKC activation<span class="elsevierStyleSup">49</span>&#46; The VEGF signalling cascade in podocytes and endothelial cells was selectively inhibited by hyperglycaemia<span class="elsevierStyleSup">49</span>&#46; The increase in glucose and diabetes would cause higher podocyte apoptosis and endothelial dysfunction&#44; partly due to a higher activation of mitogen-activated protein kinase &#40;PKC&#948;&#47;p38&#41; and SRc homology-2-domain-containing phosphatase-1 &#40;SHP-1&#41; overexpression<span class="elsevierStyleSup">49</span>&#46; In addition&#44; SHP-1 negatively regulates VEGFR2 and the insulin receptor<span class="elsevierStyleSup">49</span>&#46;</p><p class="elsevierStylePara"> Warren et al&#46; showed that hyperglycaemia reduces endothelial VEGFR2 activity in diabetes<span class="elsevierStyleSup">41</span>&#46; ROS generation caused by hyperglycaemia was observed to induce VEGFR2 activation and its subsequent breakdown&#44; notwithstanding the VEGF-A<span class="elsevierStyleSup">41</span>&#46; This would alter the normal response of endothelial cells to circulating VEGF-A due to lower receptor availability&#46; By blocking ROS production with antioxidants&#44; VEGFR2 availability and the lack of endothelial response to VEGF-A caused by hyperglycaemia were reverted<span class="elsevierStyleSup">41</span>&#46; These results suggest that the increase in VEGF-A present from early stages of DN may be secondary to &#8220;VEGF-resistance&#8221; of the VEGFR2 caused by higher receptor breakdown in endothelial cells&#46;</p><p class="elsevierStylePara"> Jointly&#44; these publications indicate that&#44; in DN&#44; VEGF over-expression in podocytes may be stimulated in an autocrine and paracrine way by a &#8220;VEGF-resistance&#8221; state&#46; VEGF-A connections with oxidative stress at glomerular level may represent pathways with therapeutic potential&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Relationship between angiopoietins and VEGF-A&#160;in DN </span></p><p class="elsevierStylePara"> Angiopoietins&#44; which are growth factors involved in angio-genesis&#44; have been related to DN<span class="elsevierStyleSup">15&#44;36</span>&#46; Plasma levels of angiopoietin 2 are high in diabetic humans and mice&#44; thus altering the angiopoetin-1&#47;angiopoetin-2 ratio&#46; Diabetic mice with lower angiopoietin 1 levels showed aberrant angiogenesis&#44; hyperfiltration&#44; glomerulomegaly and albuminuria&#44; accompanied by VEGF-A and phosphorylated VEGFR2 overexpression&#46; Alterations caused by reduced angiopoietin 1 were seen to be partially prevented by restoring its expression in podocytes in transgenic mice<span class="elsevierStyleSup">36</span>&#46; These experiments show the importance of angiopoietins and their relationship with VEGF-A in DN pathophysiogenesis&#46; Modification of protein expression at the glomerular level &#40;by manipulating the cells that produce these proteins&#41; is a therapeutic alternative<span class="elsevierStyleSup">36</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Relationship between VEGF-A and nitric oxide&#160;in&#160;DN </span></p><p class="elsevierStylePara"> VEGF-A stimulates NO production by means of endothelial NO synthase &#40;eNOS&#41; activation<span class="elsevierStyleSup">15&#44;35&#46;50</span>&#46; The effects of VEGF-A on vasodilation and on the vascular permeability increase are mediated by the increase in eNOS-dependent NO<span class="elsevierStyleSup">15&#44;27&#44;35&#44;50</span>&#46; Under normal conditions&#44; VEGF-A induces eNOS activation and an increase in NO&#59; this increase negatively regulates VEGF-A and CTGF&#44; inhibiting ECM build-up<span class="elsevierStyleSup">15</span>&#46; In diabetes&#44; this relationship changes&#58; the increase in VEGF-A coexists with lower eNOS activity&#44; and there is VEGF-A and NO decoupling<span class="elsevierStyleSup">50</span>&#46; Along the lines of this theory&#44; a study of diabetic mice with no eNOS reported an increase in VEGF-A expression and severe DN<span class="elsevierStyleSup">50</span>&#46; We showed that VEGF overexpression in podocytes&#44; associated with an absence of eNOS&#44; induced indistinguishable changes in advanced DN<span class="elsevierStyleSup">35</span>&#46; In the absence of diabetes&#44; these transgenic mice developed proteinura&#44; kidney failure and nodular glomerulosclerosis<span class="elsevierStyleSup">35</span>&#46; This evidence suggests that alterations in glomerular VEGF-A&#47;NO-eNOS ratio are critical and very dangerous&#44; highlighting these events and their relationship with VEGF-A as treatment targets at the glomerular level&#46;</p><p class="elsevierStylePara"> Endothelial NO deficiency secondary to reduced eNOS activity may also associate insulin resistance mechanisms with endothelial dysfunction<span class="elsevierStyleSup">47&#44;48</span>&#46; Endothelial cells express insulin receptors&#46; By means of eNOS activation&#44; these receptors control vascular tone by inducing vasodilation&#46; For example&#44; in patients with diabetes there are alterations in eNOS activation&#44; establishing a relationship between NO and endothelial insulin resistance<span class="elsevierStyleSup">47-49</span>&#46; These findings suggest that VEGF-A and the glomerular NO&#47;eNOS ratio may be implied in the insulin resistance status associated with prediabetes&#44; diabetes and CKD&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conclusions </span></p><p class="elsevierStylePara"> Population studies reveal an increasing prevalence of type 2 diabetes worldwide&#44; which suggests that DN will become an even more serious problem&#46; It is imperative to look for alternatives for the diagnosis&#44; prevention and treatment of DN&#46; Going further in the study of molecular pathways with therapeutic potential&#44; such as angiogenic factors&#44; the glomerular VEGF resistance status&#44; insulin resistance in podocytes&#44; the VEGFR2&#47;nephrin ratio&#44; VEGF&#47;insulin receptors &#47;nephrin ratio&#44; and the VEGF&#47;NO-eNOS ratio&#44; may provide solutions to the urgent problem of DN in the world&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Key concepts </span></p><p class="elsevierStylePara"> 1&#46; Diabetes mellitus and CKD prevalence have increased in recent decades&#46; The most frequent isolated cause of CKD is DN&#46; Factors related to DN development are&#58; age over 65&#44; uncontrolled hyperglycaemia&#44; hypertension blood pressure&#44; dyslipidaemia&#44; male gender&#44; smoking habit&#44; family history&#44; and Hispanic or Afro-American origin&#46;</p><p class="elsevierStylePara"> 2&#46; Glucose directly and indirectly stimulates VEGF-A cell expression&#46; In DN&#44; there is a systemic and glomerular increase in VEGF-A&#44; but glomerular VEGF-A and the glomerular VEGF-A&#47;NO-eNOS ratio are key factors in DN pathophysiogenesis&#46;</p><p class="elsevierStylePara"> 3&#46; Endothelial cells and podocytes express insulin receptors&#46; Nephrin is essential for the action of the insulin receptor in podocytes&#59; its activation is related to VEGF-A&#46; VEGFR2 and nephrin interact in podocytes&#46; Insulin receptors&#44; nephrin and VEGF-A receptors may be mechanistically related to DN and insulin resistance&#46;</p><p class="elsevierStylePara"> 4&#46; In DN&#44; VEGF overexpression in podocytes may be stimulated in an autocrine and paracrine way by a &#8220;VEGF-resistance&#8221; status&#44; in which PKC and ROS would be involved&#46; VEGF-A connections to oxidative stress at the glomerular level may represent pathways with a therapeutic potential for DN&#46;</p><p class="elsevierStylePara"> 5&#46; Angiogenic factors&#44; such as VEGF-A and angiopoietins&#44; VEGF resistance status&#44; insulin resistance in podocytes&#44; VEGFR2&#47;nephrin ratio&#44; VEGF-A&#47;insulin receptors&#47;nephrin ratio&#44; and VEGF&#47;NO-eNOS ratio&#44; represent glomerular pathways that have a crucial significance and may be potential treatment targets for DN&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Acknowledgements </span></p><p class="elsevierStylePara"> We would like to thank Mait&#233;n Fern&#225;ndez Ver&#243;n&#44; Facultad de Arquitectura&#44; Dise&#241;o y Urbanismo &#91;School of Architecture&#44; Desig n and Urbanism&#93;&#44; Universidad de Buenos Aires &#91;University of Buenos Aires&#93;&#44; Argentina for collaborating in the design of the Figures&#46; We would also like to thank Eco&#46; Patricio &#193;lvarez&#44; UNEMI &#40;Universidad Estatal de Milagro &#91;State University of Milagro&#93;&#41; for helping in the publication processes and Gonzalo Fern&#225;ndez Ver&#243;n for the language review&#46;</p><hr></hr><p class="elsevierStylePara"> Sent for Review&#58; 05 Nov 2014 <br></br> Accepted on&#58; 03 Dec 2014</p><p class="elsevierStylePara"><a href="http&#58;&#47;&#47;dx&#46;doi&#46;org&#47;10&#46;3265&#47;Nefrologia&#46;pre2014&#46;Dec&#46;12808" class="elsevierStyleCrossRefs">http&#58;&#47;&#47;dx&#46;doi&#46;org&#47;10&#46;3265&#47;Nefrologia&#46;pre2014&#46;Dec&#46;12808</a></p><p class="elsevierStylePara"> &#42; <span class="elsevierStyleItalic">Corresponding author</span>&#46;<br></br> Delma Veron&#44; School of Health Sciences&#44; <br></br> Universidad Estatal de Milagro&#44; Ciudadela Universitaria&#44; <br></br> UNEMI&#44; Kil&#243;metro 1 &#189; V&#237;a KM 26&#46;&#44; 091050&#44; Milagro&#44; Guayas&#44; Ecuador&#46; <br></br> Tel&#46;&#58; &#40;593&#41; 46038456<br></br><span class="elsevierStyleItalic">E-mail&#58;</span> delveron&#64;gmail&#46;com&#59; <a href="mailto&#58;proyectond&#64;hotmail&#46;com" class="elsevierStyleCrossRefs">proyectond&#64;hotmail&#46;com</a></p>"
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          "palabras" => array:19 [
            0 => "Nefropat&#237;a diab&#233;tica"
            1 => "VEGF-A"
            2 => "VEGF"
            3 => "Podocito"
            4 => "Endotelio"
            5 => "Barrera de filtraci&#243;n glomerular"
            6 => "VEGFR2"
            7 => "Receptores de VEGF"
            8 => "&#211;xido n&#237;trico"
            9 => "Receptor de insulina"
            10 => "Angiopoietina"
            11 => "ROS"
            12 => "Ri&#241;&#243;n"
            13 => "Diabetes mellitus"
            14 => "Proteinuria"
            15 => "Sudam&#233;rica"
            16 => "Angiog&#233;nesis"
            17 => "Enfermedad renal cr&#243;nica"
            18 => "Insulinorresistencia"
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          "clase" => "keyword"
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          "identificador" => "xpalclavsec503475"
          "palabras" => array:15 [
            0 => "Diabetic nephropathy&#44; VEGF-A&#44; VEGF"
            1 => "Podocyte"
            2 => "Endothelium"
            3 => "Glomerular filtration barrier"
            4 => "VEGFR2&#44; VEGF receptors"
            5 => "Nitric oxide"
            6 => "Insulin receptor"
            7 => "Angiopoietin"
            8 => "ROS"
            9 => "Kidney"
            10 => "Diabetes mellitus proteinuria"
            11 => "South America"
            12 => "Angiogenesis"
            13 => "Chronic kidney disease"
            14 => "Insulin resistance"
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        "resumen" => "<p class="elsevierStylePara"> La prevalencia de diabetes mellitus aument&#243; en el &#250;ltimo siglo y se estima que el 45&#37; de los pacientes&#44; no estar&#237;an diagnosticados&#46; En Sudam&#233;rica la prevalencia de diabetes y de enfermedad renal cr&#243;nica &#40;ERC&#41; increment&#243;&#44; existiendo gran disparidad entre los pa&#237;ses respecto al acceso a di&#225;lisis&#46; En Ecuador es una de las principales causas de mortalidad&#44; principalmente en las provincias ubicadas en la costa del oc&#233;ano Pac&#237;fico&#46; La mayor causa aislada de ingreso a di&#225;lisis es la nefropat&#237;a diab&#233;tica &#40;ND&#41;&#46; Aun utilizando las mejores opciones terap&#233;uticas para la ND&#44; el riesgo residual de proteinuria y de ERC terminal permanece elevado&#46; En esta revisi&#243;n describimos la importancia del problema en el mundo y en nuestra regi&#243;n&#46; Analizamos estudios moleculares y celulares relevantes que indican la crucial importancia de eventos glomerulares en el desarrollo y en la evoluci&#243;n de la ND y en la insulinorresistencia&#46; Incluimos conceptos anat&#243;micos&#44; fisiopatol&#243;gicos y cl&#237;nicos b&#225;sicos&#44; desarrollando especial &#233;nfasis en el rol de factores angiog&#233;nicos como el factor de crecimiento vascular endotelial &#40;VEGF-A&#41; y su relaci&#243;n con el receptor de insulina&#44; la sintasa endotelial de &#243;xido n&#237;trico-&#243;xido n&#237;trico &#40;eNOS&#41; y las angiopoietinas&#46; En el transcurso del texto proponemos diversas v&#237;as&#44; que a nuestro entender tienen potencial terap&#233;utico&#46; Profundizar en el estudio del VEGF-A y las angiopoietinas&#44; el estado de VEGF resistencia glomerular&#44; la relaci&#243;n del receptor 2 de VEGF&#47; nefrina&#44; VEGF&#47;receptores de insulina&#47;nefrina&#44; la relaci&#243;n VEGF&#47;eNOS-ON a nivel glomerular podr&#237;a aportar soluciones al acuciante problema de la ND en el mundo y generar nuevas alternativas de tratamiento&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"> The prevalence of diabetes mellitus increased in the last century&#44; and it is estimated that 45&#37; of patients have not yet been diagnosed&#46; In South America&#44; diabetes and chronic kidney disease &#40;CKD&#41; prevalence increased&#44; and there is great disparity regarding access to dialysis among these countries&#46; In Ecuador&#44; it is one of the major causes of mortality&#44; mainly in provinces located on the Pacific coast&#46; The main cause of admission to dialysis is diabetic nephropathy &#40;DN&#41;&#46; Even when the best therapeutic options for DN are used&#44; the residual risk of proteinuria and end-stage CKD continues to be high&#46;</p> <p class="elsevierStylePara"> In this review&#44; we describe the magnitude of the issue both worldwide and locally&#46; We analysed relevant molecular and cellular studies&#44; which indicate the crucial significance of glomerular events in DN development and progress and in insulin resistance&#46; We included basic anatomical&#44; pathophysiological and clinical concepts&#44; with special emphasis on the role played by angiogenic factors&#44; such as vascular endothelial growth factor &#40;VEGF-A&#41; and its relationship with the insulin receptor&#44; endothelial nitric oxide synthase &#40;eNOS&#41; and angiopoietins&#46; Throughout the text&#44; we suggest several pathways&#44; which&#44; in our opinion&#44; have therapeutic potential&#46; Going further in the study of VEGF-A and angiopoietins&#44; glomerular VEGF resistance status&#44; the VEGF receptor 2&#47;nephrin ratio&#44; VEGF&#47;receptors of insulin&#47;nephrin ratio&#44; the VEGF&#47;NO-eNOS ratio at glomerular level may provide solutions to the urgent issue of DN worldwide and lead to new treatment alternatives&#46;</p>"
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          "en" => "– In Ecuador&#44; mortality caused by diabetes mellitus was higher in the provinces of Guayas&#44; Los R&#237;os and Manab&#237;&#44; located on the Pacific coast&#46; Map shows the mortality rate due to diabetes mellitus &#40;deaths&#47;100&#44;000 individuals per year&#44; INEC &#91;Instituto Nacional de Estad&#237;sticas y Censos - National Institute of Statistics and Census of Ecuador&#93; 2011&#41;&#46; This figure is part of a figure originally published by Neira-Mosquera et al&#46;6&#44; with minor modifications &#40;authorised reproduction&#41;&#46;"
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          "en" => "– Schematic representation of the glomerulus&#44; the glomerular filtration barrier &#40;GFB&#41; composed of podocytes&#160;&#40;P&#41;&#44;&#160;the&#160;glomerular basal membrane &#40;GBM&#41;&#44; and the endothelium&#46; Plasma ultrafiltration passes through the GFB &#40;black arrow&#41; to reach the urinary space &#40;US&#41;&#46; Podocytes &#40;green&#41; make contact with several glomerular capillaries &#40;represented as red circles&#41; and the intraglomerular mesangium &#40;M&#41;&#46; The GBM &#40;black line&#41; wraps the capillaries and surrounds the mesangium&#46; The glomerular endothelium is represented by a discontinuous light-blue line&#44; located between the capillary lumen &#40;CL&#41; and the GBM&#44; the vascular pole in the lower part of the glomerulus&#44; the tubular pole in the upper part&#46; B&#58; Ultrastructure of the GFB observed with an electronic microscope&#58; podocytes&#44; GBM&#44; slit diaphragm &#40;SD&#41; and fenestrated endothelium&#46; Plasma ultrafiltration passes through the GFB &#40;yellow arrow&#41; from the capillary lumen &#40;CL&#41; towards the urinary space &#40;US&#41;&#46;"
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Article information

ISSN: 20132514
Original language: English

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	7	8	15
2024 October	51	30	81
2024 September	56	30	86
2024 August	59	48	107
2024 July	54	25	79
2024 June	50	32	82
2024 May	53	30	83
2024 April	60	26	86
2024 March	37	32	69
2024 February	45	30	75
2024 January	32	23	55
2023 December	28	25	53
2023 November	35	31	66
2023 October	56	28	84
2023 September	69	23	92
2023 August	56	20	76
2023 July	50	29	79
2023 June	47	20	67
2023 May	63	28	91
2023 April	20	11	31
2023 March	50	18	68
2023 February	30	19	49
2023 January	37	20	57
2022 December	46	22	68
2022 November	30	22	52
2022 October	45	36	81
2022 September	38	24	62
2022 August	46	42	88
2022 July	33	41	74
2022 June	39	31	70
2022 May	48	29	77
2022 April	55	47	102
2022 March	45	51	96
2022 February	38	40	78
2022 January	66	33	99
2021 December	63	29	92
2021 November	26	34	60
2021 October	41	36	77
2021 September	29	38	67
2021 August	41	35	76
2021 July	34	32	66
2021 June	38	29	67
2021 May	29	34	63
2021 April	75	38	113
2021 March	63	32	95
2021 February	29	10	39
2021 January	46	18	64
2020 December	25	12	37
2020 November	39	13	52
2020 October	15	16	31
2020 September	39	4	43
2020 August	47	12	59
2020 July	54	10	64
2020 June	46	8	54
2020 May	63	12	75
2020 April	51	20	71
2020 March	64	29	93
2020 February	91	20	111
2020 January	83	25	108
2019 December	80	33	113
2019 November	66	24	90
2019 October	52	20	72
2019 September	77	21	98
2019 August	58	30	88
2019 July	50	33	83
2019 June	60	29	89
2019 May	58	20	78
2019 April	68	31	99
2019 March	60	20	80
2019 February	24	7	31
2019 January	42	25	67
2018 December	90	35	125
2018 November	99	14	113
2018 October	129	20	149
2018 September	88	15	103
2018 August	50	13	63
2018 July	58	17	75
2018 June	49	17	66
2018 May	46	9	55
2018 April	80	9	89
2018 March	32	9	41
2018 February	44	7	51
2018 January	40	8	48
2017 December	39	9	48
2017 November	64	12	76
2017 October	52	4	56
2017 September	47	10	57
2017 August	54	10	64
2017 July	40	18	58
2017 June	47	14	61
2017 May	48	12	60
2017 April	52	24	76
2017 March	44	7	51
2017 February	53	11	64
2017 January	54	6	60
2016 December	98	11	109
2016 November	112	14	126
2016 October	124	16	140
2016 September	174	9	183
2016 August	310	0	310
2016 July	256	0	256
2016 June	198	0	198
2016 May	204	0	204
2016 April	171	0	171
2016 March	165	0	165
2016 February	193	0	193
2016 January	316	0	316
2015 December	336	1	337
2015 November	310	1	311
2015 October	496	5	501
2015 September	493	84	577
2015 August	726	781	1507
2015 July	441	0	441
2015 June	260	0	260
2015 May	729	102	831
2015 April	65	0	65

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