microRNAs in the kidney: Novel biomarkers of Acute Kidney Injury

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Laura García-Bermejo" "autores" => array:6 [ 0 => array:3 [ "nombre" => "Elia" "apellidos" => "Aguado-Fraile" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 1 => array:3 [ "nombre" => "Edurne" "apellidos" => "Ramos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 2 => array:3 [ "nombre" => "Elisa" "apellidos" => "Conde" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 3 => array:3 [ "nombre" => "Macarena" "apellidos" => "Rodríguez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 4 => array:3 [ "nombre" => "Fernando" "apellidos" => "Liaño" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] 5 => array:4 [ "nombre" => "M. Laura" "apellidos" => "García-Bermejo" "email" => array:1 [ 0 => "garciabermejo@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Patología de Sistemas y Cáncer, Hospital Universitario Ramón y Cajal. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, " "etiqueta" => "a" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Ramón y Cajal. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, " "etiqueta" => "b" "identificador" => "affb" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Los microARN en el riñón: nuevos biomarcadores de la lesión renal aguda" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12198_16025_49916_en_f110.12198_i.jpg" "Alto" => 2053 "Ancho" => 2118 "Tamanyo" => 671722 ] ] "descripcion" => array:1 [ "en" => "microRNA biogenesis, function and secretion." ] ] ] "textoCompleto" => "microRNAs miRNAs are small (20-25 nucleotides) non-coding RNAs that have radically changed our understanding of gene post-transcriptional regulation. They are fine tuners of gene expression and more than 90% of the genes in mammals are submitted to their control, participating in almost every cellular function. Moreover, their deregulation is frequently associated with disease development.1More than 2000 miRNAs have been described in the human genome,2 a number comparable to the known number of transcription factors or other regulatory proteins. Moreover miRNAs show very specific expression patterns among tissues and cell types.Their mechanism of action is based on recognition of small sequences in their target mRNAs. This feature makes it possible for one miRNA to regulate hundreds of target mRNAs and that one mRNA can be regulated by several miRNAs. This dynamic regulation has unveiled them as key regulators of a wide range of cellular events, including rapid responses to stress.1 microRNA Biogenesis miRNAs are mainly transcribed by RNA polymerase II as longer primary transcripts called pri-miRNAs. miRNAs genes are often located in non coding DNA regions and they are frequently organized in clusters. Clustered miRNAs are transcribed as a single, longer pri-miRNA which generates several functional miRNAs by subsequent processing. miRNAs genes can also be found in protein coding genes, specially located inside introns. In these cases, splicing of the coding mRNAs leads to generation of the functional miRNA. As other transcripts produced by RNApolymerase II, pri-miRNAs present 5´Cap and 3´Poly-A Tail.Pri-miRNAs molecules form imperfect stem-loop structures that can be recognized by a processing complex formed by the RNAse III enzyme Drosha and the RNA binding protein (RBP) DGCR8. Stem-loop double stranded structures of pri-miRNAs are recognized by DGCR8, which guides the positioning of Drosha. This catalytic centre cleaves pri-miRNAs liberating a hairpin RNA molecule of 70-100 nucleotides known as pre-miRNA.Pre-miRNAs are exported to the cytoplasm by the nuclear export receptor Exportin 5 in a Ran-GTP dependent manner. Once in the cytoplasm pre-miRNAs are further processed by another RNAse III enzyme called Dicer. A new cleavage produces a double stranded RNA molecule of 22 nucleotides. One of the strands (the mature miRNA) is transferred to the Argonaute protein to conform the RNA Induced Silencing Complex (RISC). The other strand (often called minor, passenger or *strand) is frequently degraded. Strand selection mechanism has not been completely elucidated yet. However, it has been proposed that the strand with the less stable base-pairing in its 5´end is often chosen as guide strand to be loaded in the RISC complex.RISC complex is the key effector of miRNA regulation. This complex, joined to other controlling factors, is responsible for driving mRNA degradation or translation repression, as will be further detailed in following sections.1,3 miRNA Target Recognition and Function Once loaded into the RISC complex, miRNAs recognize their target mRNAs by base-pair complementarity. Target sequences are mainly located in the 3´ untranslated region (UTR) of mRNAs. However, functional miRNA binding sites can also be found in the 5´ UTR and open reading frame regions.Nucleotides in positions 2-8, called seed sequence, are essential for pairing with the target mRNA and miRNA function. In the case of perfect complementarity of the seed sequence of the miRNA with the target sequence, miRNAs act as a short interfering RNA (siRNA) promoting mRNA cleaving by RISC complex. This mechanism is principally found in plants but is very rare in mammals.When pairing with target sequences is partially complementary, which is the most frequent mechanism in mammals, miRNA regulation is produced by mRNA translation repression or degradation. However this degradation process is different and involves recruitment of deadenylase complexes that remove or shorten the poly-A tail of the target transcript. Poly-A tail shortening induces decapping of the 5´ extreme of the transcript and uncapped mRNAs are rapidly degraded by 5´ to 3´ exoribonucleases (Figure 1).1,3Although the contribution rate of mRNA decay and translational repression to miRNA action is a controversial topic, it seems clear that target degradation provides a major contribution to silencing in mammal cells. In this regard, it has been estimated that mRNA decay is present in 85% of the miRNA regulation process whereas 15% corresponds to translational repression.3,4 miRNA Decay and Turnover Accumulative evidence reveals that different miRNAs present distinct and inherent half-lives that could be encoded by their sequence or can be determined after maturation by post-transcriptional mechanisms such as uracile and adenosine addition to their 3´end.Half-lives of some miRNAs could reach many hours or even days in some organs like the liver or the heart.5,6 However, their ability to regulate rapid cell responses to environmental signals makes this slow turnover rate not appropriate for every context. Indeed, some miRNAs expressed in the retina and involved in darkness adaptation present a half-life of approximately 1 hour.7These interesting data point out that more attention needs to be focused on miRNA turnover as miRNA half-life regulation could emerge as a potential critical step in miRNA function. Indeed, miRNA decay regulation is one of the big challenges in miRNA biology for the next years. microRNAs IN KIDNEY Due to the relevance of miRNA function and implication in a wide range of processes such as organ development, homeostasis and pathophysiology, miRNA studies in kidney development and function have emerged as a field of intense research during the last few years. microRNAs in Normal Kidney Function and Development Several profiling studies have revealed microRNA profiles related to specific organs, including the kidney. These studies indicate that miR-146a, miR-886, miR-192, miR-194, miR-204, miR-215 and miR-216 are renal-specific microRNAs. In addition, let-7a-g, miR-196a/b, miR-10a/b, miR-130, miR146, miR-21, miR-200a, miR-30a-e and miR-872 are highly expressed in renal tissue.8-11microRNAs are essential for kidney development. In fact, lack of miRNA activity causes defects in kidney terminal differentiation such as decreased proliferation rate, aberrant nephron patterning and delayed terminal differentiation of kidney tubules. In this regard, miR-30 and miR-200 family strictly regulate the temporal and spatial expression pattern of transcription factors involved in pro-nephron maturation.12Loss of microRNAs in nephron progenitors leads to early depletion of this cell population as renal growth progresses. These effects are especially due to the regulation by miR-10a, miR-106b and miR-17-5p of Bim, a pro-apoptotic factor which increases its expression levels when miRNAs are depleted.13On the other hand, some microRNAs have been related to kidney senescence. Particularly, overexpression of miR-335 and miR-34a in mesangial cells leads to premature senescence of this cell population by the regulation of mitochondrial antioxidative enzymes.14Studies based on DICER knockdown in podocytes, juxtaglomerular cells and proximal tubules have unveiled the role of miRNAs in kidney function maintenance as well as specific miRNA roles in each kidney compartment. KO of DICER in glomerulus results in progressive loss of podocyte function leading to proteinuria and kidney function impairment and ultimately leading to animal death. Three microRNAs in particular have been identified as contributors to this renal failure (miR-23b, miR-24 and miR-26a).13,15 In addition, Drosha ablation in podocytes results in proteinuric renal disease and collapsing glomerulopathy.16DICER deletion in juxtaglomerular cells produces acute loss of this cell type leading to an abrupt decrease of renin expression in kidney and deregulation of blood pressure.17Several microRNAs have also been unveiled as critical regulators of kidney function and homeostasis maintenance. For instance, miR-320a is a direct regulator of Aquoporin 1 and 4, which are integral membrane transporters involved in water homeostasis.18 Moreover, the Na/H exchange factor-1, a regulator of ion transport in apical membrane, is a target gene of miR-200b.19All these studies indicate that miRNAs play critical roles in normal renal function and physiology maintenance and when altered, may lead to renal diseases.  microRNAs in Kidney Disease Specific miRNAs deregulation has been linked to renal disease development. For example, miR-192 has been identified as a critical regulator of collagen production in diabetic nephropathy.20 Studies in renal biopsies from diabetic patients have shown that miR-192 is poorly expressed in renal tissue. This downregulation is directly correlated with tubulointerstitial fibrosis and low glomerular filtration rate (GFR) in diabetic patients.21Several microRNAs have been related to polycystic kidney disease (PCK). miR-10a, miR30a-5p, miR-96, miR-126-5p, miR-182, miR-200a, miR204, miR-429 and miR-488 were downregulated in a Pkd1 -/- mouse model.22 Moreover, miR-15 expression was decreased in a rat model of PCK. Reduction of this microRNA increases the expression of Cdc25A, a regulator of cell cycle, promoting cyst growth.23microRNA deregulation has also been associated with renal carcinoma. miRNA profiling experiments demonstrated that miR-28, miR-185, miR-7-2 and let-7f-224 and miR-155, miR-210, miR-592, miR-34b, miR-224, miR142-3p, miR-185, miR-34a, and miR-21 were modulated in renal carcinoma tissue samples.25 All these microRNAs show target genes enriched in angiogenesis, hypoxia, apoptosis, tumorogenesis, invasion and metastasis pathways, in agreement with the pathological context where they have described.26On the other hand, the miR-200 family are repressors of E-cadherin during epithelial to mesenchimal transition (EMT), promoting cell migration and invasion during metastasis.27,28 In addition, miR-200a and miR-141 are involved in EMT and fibrosis mediated by TGFb1 in vivo and in vitro, and have an important implication in renal fibrosis development as demonstrated with animal experimental models.29 These miRNAs could be considered as novel therapeutic target in EMT-associated nephropathies including chronic kidney diseases, where efficient treatments are still not available. miRNAs in Renal Ischemia/Reperfusion The clear role of miRNAs in kidney function and nephropathies and the ability of miRNAs to regulate rapid responses to stress and injury have unveiled microRNAs as potential key regulators of kidney responses to acute damage, such as Acute Kidney Injury following renal Ischemia/Reperfusion (I/R).miRNAs involvement in kidney response to I/R was undoubtedly demonstrated by DICER KO experiments in proximal tubular cells. DICER KO mice showed normal renal function and proximal tubule structure in basal conditions. However, general downregulation of miRNAs conferred a protection against I/R injury, since DICER KO animals subjected to I/R exhibited significantly better renal function, less tissue damage, lower tubular apoptosis and improved survival compared to wild-type animals.30Global expression profiling experiments in mice undergoing renal I/R have identified a signature of 9 microRNAs (miR-21, miR-20a, miR-146a, miR-199a-3p, miR-214, miR-192, miR-187, miR-805, and miR-194) which are differentially expressed in kidney compared to sham controls.31 Moreover, a more recent work from the same group demonstrates that microRNA signature after I/R is different in operated animals when compared to sham controls and these differences are maintained and evolve along time. Their data strongly evidence that altered miRNAs after I/R could be considered as new biomarkers for renal I/R injury.32In addition to the miRNAs signature of renal response to I/R, miRNAs also have been implicated in protection against ischemic injury, showing that these molecules are potential novel therapeutic targets in this context. In fact, our lab recently demonstrated that miR-127 is a regulator of the proximal tubule cell response to I/R injury. Overexpression of this microRNA in an in vitro model of I/R demonstrates that miR-127 prevents focal adhesion complex disassembly and thigh junction disruption provoked by I/R. Moreover, kinesin familiy member 3B, a component of the Kinesin II complex involved in intracellular vesicle trafficking, is a target gene of miR-127 in proximal tubule cells during I/R, with important implications in kidney function.33 Based on these results, the potential role of miR-127 in the pathophysiology of ischemic proximal tubule injury is summarized in Figure 2.Moreover, Liu F. et al. demonstrate that miR-210, a well established miRNA regulated by hypoxia, is involved in angiogenesis regulation during renal I/R by activating VEGF and its receptor VEGFR2 expression, contributing to ischemic injury recovery.34 Regarding to vascular compartment involvement in renal I/R response, miRNAs contained in vesicles derived from endothelial progenitors protect renal cells from I/R injury. Intravenous injection of microvesicles confers functional and morphologic protection of renal cells by enhancing tubular cell proliferation and reducing apoptosis and leukocyte infiltration. These miRNAs also protect kidney from chronic damage progression by inhibiting glomerulosclerosis and tubulointerstitial fibrosis. Thus, vesicle-derived miRNAs contribute to reprogram resident renal cells to a regenerative program after I/R injury.35 CIRCULATING microRNAs AS NOVEL BIOMARKERS Even though the initial studies proposed that miRNAs were only present inside the cell, it has been demonstrated that they can also be secreted to the extracellular environment with potential functional consequences.36 This secretion process has resulted in their detection in a wide range of cell-free body fluids such as breast milk, urine or serum.37miRNA secretion seems a highly regulated process and selection of miRNAs which can be secreted is not a random process. On the other hand, as mentioned before, miRNA deregulation has been associated with the development of a wide range of pathologies. Due to these features, physiological or pathological regulation of intracellular miRNAs may also modify the panel of secreted miRNAs. Indeed, changes in serum miRNAs profiles have been unveiled as useful markers of a wide range of diseases including cancer, cardiovascular disease, stroke and nephropathies as well as  physiological states such as pregnancy.38Moreover, serum miRNAs have demonstrated great stability and resistance to aggressive conditions such as RNAse treatment, or drastic pH changes.39 The mechanism underlying this unexpected miRNA stability in serum is still not completely understood, but it has been evidenced that circulating microRNAs are released from cells in membrane vesicles which protects them from the environment. Vesicles proposed to be carriers of circulating microRNAs include exosomes, which are 50-90nm vesicles released by exocytosis from multivesicular bodies (MVB)36,40 as well as larger microvesicles up to 1µm.41,42 Furthermore, recent studies have demonstrated that serum circulating miRNAs can also be carried by Argonaute2 proteins.43Taken together, all these features demonstrate that serum circulating miRNAs achieve nearly all the required characteristics for an ideal biomarker. Their presence in a peripheral fluid allows diagnosis by minimum invasive methods and samples can be easily and routinely obtained in clinical practice. In addition to their high stability in fresh samples, several studies have demonstrated that miRNAs maintain stability and reliability in long-term stored serum samples and in samples conserved at room temperature for hours.39 Moreover, they can be easily quantified by qRT-PCR, with affordable technical effort. These characteristics, joined to their tissue and cell type specificity, have revealed circulating miRNAs as promising biomarkers for more accurate diagnosis and monitoring of diseases.Regarding the advantage of circulating miRNAs as precise biomarkers in comparison to the ones available up to now, it is important to notice that miRNAs could belong to the pathophysiological mechanisms responsible for diseases, including renal diseases. Therefore, miRNAs could provide the clinician with critical additional information that is currently not accessible and they could also be considered as novel therapeutic targets. CIRCULATING microRNAs AS AKI BIOMARKERS Despite the intense research in the circulating miRNAs field of the last years, publications about their role as AKI biomarkers are still scarce. However, during the last two years some articles have started to point out this issue.Lorenzen JM et al. in 2011 revealed that miR-210 was upregulated in plasma samples of a cohort of 77 AKI patients compared to healthy controls. Moreover, plasma levels of this microRNA could predict patient survival 4 weeks after initiation of Renal Replacement Therapy (RRT).44In addition, miR-21 and miR-155 are upregulated in renal tissue after I/R or toxic injury, correlating with a lower expression in blood and urinary supernatants. Moreover, these microRNAs were also modulated in urine samples of AKI patients compared to healthy volunteers. Bioinformatics analysis of the target genes of these microRNAs evidenced that they were enriched in pathways related to apoptosis and cell proliferation.45A recent publication by Lan YF et al., demonstrates that miR-494 is a regulator of the renal inflammatory response as well as apoptosis after I/R injury. Moreover, detection of this miRNA in urine showed that miR-494 expression is 60 fold higher in AKI patients compared to healthy controls.46In addition to these reports, our group has identified and validated a panel of 10 serum miRNAs, including miR-101-1, miR-127-3p, miR-210, miR-126, miR-26b, miR-29a, miR-146a, miR-27a, miR-93* and miR-10a, as biomarkers of AKI, using cohorts of intensive care units (ICU) patients with AKI and cardiac surgery with cardiopulmonary bypass patients. ROC analysis for diagnostic value of the panel demonstrated sensitivity and specificity close to 100%. Moreover, serum miRNAs detect AKI development before serum creatinine increases, becoming early diagnostic tools. These miRNAs provide additional valuable clinical information such as AKI severity, AKI origin (pre-renal or intrinsic) or AKI aetiology. Moreover, serum miRNAs could be considered biomarkers of AKI predisposition since they can predict AKI development when when microRNA are estimated before cardiac surgery.47All these studies demonstrated that miRNAs could be precise biomarkers of AKI diagnosis useful in clinical practice, offering valuable additional information in comparison with classical biomarkers. Since miRNAs are capable of indicating survival, recovery, AKI origins or AKI aetiologies, they could significantly contribute to improve AKI patient management. FUTURE PERSPECTIVES OF miRNAs IN AKI The information provided here identifies miRNAs as very promising molecules for increasing the knowledge of pathophysiological mechanisms underlying kidney diseases and very powerful tools for improving clinical management of renal patients.miRNAs identification and validation as biomarkers for nephropathies will contribute to more precise diagnostics and prognostics as well as will provide valuable additional information for patient handling. Although it was not the main topic of this review, miRNAs could also be considered as novel therapeutic targets in renal diseases. In this regard, the improved knowledge of miRNAs involved in renal I/R injury and recovery could be a key point for developing new therapeutic approaches to prevent AKI, reduce chronic renal disease derived from acute episodes and improve outcome.Identification of microRNAs as novel biomarkers for AKI could drastically change current clinical practice allowing earlier detection and better patient monitoring and handling. Therefore, taking into account the reported results and our findings, the use of miRNAs in AKI clinical practice can be proposed, based on the dynamic model of AKI by Pickering and Endre48 (Figure 3). This model establishes the concept of Phase-Specific AKI Biomarkers.miRNAs could be considered Phase-1 Biomarkers since they could identify patients in risk of AKI development,47 thus allowing the application of preventive strategies. miRNAs could also be Phase 2 Biomarkers since miRNAs expression correlates with AKI diagnosis before creatinine increases, permitting the application of early therapeutic interventions. Phase 3 Specific Biomarkers are able to monitor injury and repair. In this regard, serum miRNA levels correlate with severity and different recovery degrees.45,47 Finally, Phase 4 Specific Biomarkers, including serum miRNAs, will identify AKI outcomes such as CKD development, RRT requirement or survival.44-47In summary, miRNAs have started to emerge as key players in many relevant diseases, including nephropathies. This review has aimed to introduce and overview miRNAs as exciting molecules in Experimental Nephrology and promising tools in Clinical Nephrology.  KEY CONCEPTS<ul><li>microRNAs are small RNA molecules which are key regulators of gene expression. </li><li>microRNAs are involved in normal kidney function and development as well as in development of renal pathologies.</li><li>microRNAs can be detected in peripheral body fluids such as serum or urine. </li><li>Circulating microRNAs detected in body fluids are novel biomarkers of renal diseases, including Acute Kidney Injury.</li></ul> FUNDING This work was supported by grants FIS PS09/02183 and PS12/00094 by Instituto de Salud Carlos III (ISCIII) and Ayuda Intramural FIBIO HRYC 122/2009. EAF is supported by CAM-CIFRA (S2010/BMD-2378), ER is funded by REDINREN (RD12/0021/0020), MR is recipient of contract from ISCIII (CA11/00491). We are also grateful to F. Jiménez for his valuable help with figures editing. Conflicts of interest The authors declare that they have no conflicts of interest related to the contents of this article.<a href="grande/12198_16025_49916_en_f110.12198_i.jpg" class="elsevierStyleCrossRefs"><img src="12198_16025_49916_en_f110.12198_i.jpg" alt="microRNA biogenesis, function and secretion. "></img></a>Figure 1. microRNA biogenesis, function and secretion. <a href="grande/12198_16025_49918_en_f210.12198_i.jpg" class="elsevierStyleCrossRefs"><img src="12198_16025_49918_en_f210.12198_i.jpg" alt="miR-127 as potential mediator of AKI pathophysiology in proximal tubule cells."></img></a>Figure 2. miR-127 as potential mediator of AKI pathophysiology in proximal tubule cells.<a href="grande/12198_16025_49919_en_f310.12198_i.jpg" class="elsevierStyleCrossRefs"><img src="12198_16025_49919_en_f310.12198_i.jpg" alt="Circulating miRNAs as useful biomarkers of AKI in clinical practice."></img></a>Figure 3. Circulating miRNAs as useful biomarkers of AKI in clinical practice." "pdfFichero" => "P1-E562-S4396-A12198-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:3 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439543" "palabras" => array:1 [ 0 => "Biomarcadores" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439545" "palabras" => array:1 [ 0 => "Insuficiencia renal aguda" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439548" "palabras" => array:1 [ 0 => "microRNAs" ] ] ] "en" => array:3 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439544" "palabras" => array:1 [ 0 => "Biomarkers" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439547" "palabras" => array:1 [ 0 => "Acute kidney injury" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439550" "palabras" => array:1 [ 0 => "microRNAs" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "Los microARN son pequeñas moléculas endógenas de ARN de vital importancia para la regulación de la expresión génica. Se han convertido en los mediadores biológicos más importantes que se han caracterizado en los últimos diez años. Participan en casi todos los procesos celulares, por lo que su desregulación está asociada al desarrollo de muchas patologías, entre las que se encuentran las renales. Existen cada vez más pruebas que demuestran que los microARN son reguladores claves de la función y el desarrollo renal, aunque también se encuentran en el origen de algunas enfermedades renales. Los estudios más recientes han concluido que estas moléculas pueden ser secretadas al exterior de la célula, lo que permite que puedan ser detectadas en fluidos periféricos como la orina y el suero. Además, los microARN circulantes detectados en los fluidos corporales pueden ser biomarcadores adecuados de las enfermedades renales, entre las que se incluye la lesión renal aguda. Esta nueva generación de biomarcadores renales podría tener consecuencias importantes para la práctica clínica, ya que podrían contribuir significativamente a la mejora del manejo de los pacientes. En este trabajo se revisa la implicación de los microARN en la homeostasis y la función renal y el papel de los microARN circulantes como nuevos biomarcadores de las enfermedades renales, centrándonos en su potencial utilidad para el manejo de la lesión renal aguda." ] "en" => array:1 [ "resumen" => "microRNAs are small, endogenous RNA molecules which are critical for a new step in the regulation of the gene expression. They have become the most critical biological mediators characterized in the last ten years. microRNAs participate in almost every cellular process, therefore their deregulation is associated with the development of a wide range of pathologies, including kidney diseases. Increasing evidence demonstrates that microRNAs are key regulators of the normal kidney function and development, but they are also at the basis of several renal diseases. Recent works have established that these molecules can be secreted to extracellular environments, enabling their detection in peripheral body fluids such as urine and serum. Moreover, circulating miRNAs detected in body fluids turn into suitable biomarkers of kidney diseases, including acute kidney injury. This new generation of renal biomarkers could have a great impact in the clinical practice, significantly contributing to improve patient management. In this review, we discuss over the implication of microRNAs in normal kidney function and homeostasis as well as the role of circulating miRNAs as novel biomarkers of kidney diseases, focusing on their potential usefulness in acute kidney injury management." ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12198_16025_49916_en_f110.12198_i.jpg" "Alto" => 2053 "Ancho" => 2118 "Tamanyo" => 671722 ] ] "descripcion" => array:1 [ "en" => "microRNA biogenesis, function and secretion." ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12198_16025_49918_en_f210.12198_i.jpg" "Alto" => 833 "Ancho" => 1009 "Tamanyo" => 381194 ] ] "descripcion" => array:1 [ "en" => "miR-127 as potential mediator of AKI pathophysiology in proximal tubule cells." ] ] 2 => array:8 [ "identificador" => "fig3" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12198_16025_49919_en_f310.12198_i.jpg" "Alto" => 1339 "Ancho" => 2110 "Tamanyo" => 450487 ] ] "descripcion" => array:1 [ "en" => "Circulating miRNAs as useful biomarkers of AKI in clinical practice." ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:49 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Krol J, Loedige I, Filipowicz W. 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Los microARN en el riñón: nuevos biomarcadores de la lesión renal aguda

Elia Aguado-Frailea, Edurne Ramosa, Elisa Condea, Macarena Rodrígueza, Fernando Liañob, M. Laura García-Bermejoa

a Patología de Sistemas y Cáncer, Hospital Universitario Ramón y Cajal. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid,

b Servicio de Nefrología, Hospital Universitario Ramón y Cajal. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid,

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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">microRNAs</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">miRNAs are small &#40;20-25 nucleotides&#41; non-coding RNAs that have radically changed our understanding of gene post-transcriptional regulation&#46; They are fine tuners of gene expression and more than 90&#37; of the genes in mammals are submitted to their control&#44; participating in almost every cellular function&#46; Moreover&#44; their deregulation is frequently associated with disease development&#46;<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara">More than 2000 miRNAs have been described in the human genome&#44;<span class="elsevierStyleSup">2</span> a number comparable to the known number of transcription factors or other regulatory proteins&#46; Moreover miRNAs show very specific expression patterns among tissues and cell types&#46;</p><p class="elsevierStylePara">Their mechanism of action is based on recognition of small sequences in their target mRNAs&#46; This feature makes it possible for one miRNA to regulate hundreds of target mRNAs and that one mRNA can be regulated by several miRNAs&#46; This dynamic regulation has unveiled them as key regulators of a wide range of cellular events&#44; including rapid responses to stress&#46;<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">microRNA Biogenesis</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">miRNAs are mainly transcribed by RNA polymerase II as longer primary transcripts called pri-miRNAs&#46; miRNAs genes are often located in non coding DNA regions and they are frequently organized in clusters&#46; Clustered miRNAs are transcribed as a single&#44; longer pri-miRNA which generates several functional miRNAs by subsequent processing&#46; miRNAs genes can also be found in protein coding genes&#44; specially located inside introns&#46; In these cases&#44; splicing of the coding mRNAs leads to generation of the functional miRNA&#46; As other transcripts produced by RNApolymerase II&#44; pri-miRNAs present 5&#180;Cap and 3&#180;Poly-A Tail&#46;</p><p class="elsevierStylePara">Pri-miRNAs molecules form imperfect stem-loop structures that can be recognized by a processing complex formed by the RNAse III enzyme Drosha and the RNA binding protein &#40;RBP&#41; DGCR8&#46; Stem-loop double stranded structures of pri-miRNAs are recognized by DGCR8&#44; which guides the positioning of Drosha&#46; This catalytic centre cleaves pri-miRNAs liberating a hairpin RNA molecule of 70-100 nucleotides known as pre-miRNA&#46;</p><p class="elsevierStylePara">Pre-miRNAs are exported to the cytoplasm by the nuclear export receptor Exportin 5 in a Ran-GTP dependent manner&#46; Once in the cytoplasm pre-miRNAs are further processed by another RNAse III enzyme called Dicer&#46; A new cleavage produces a double stranded RNA molecule of 22 nucleotides&#46; One of the strands &#40;the mature miRNA&#41; is transferred to the Argonaute protein to conform the RNA Induced Silencing Complex &#40;RISC&#41;&#46; The other strand &#40;often called minor&#44; passenger or &#42;strand&#41; is frequently degraded&#46; Strand selection mechanism has not been completely elucidated yet&#46; However&#44; it has been proposed that the strand with the less stable base-pairing in its 5&#180;end is often chosen as guide strand to be loaded in the RISC complex&#46;</p><p class="elsevierStylePara">RISC complex is the key effector of miRNA regulation&#46; This complex&#44; joined to other controlling factors&#44; is responsible for driving mRNA degradation or translation repression&#44; as will be further detailed in following sections&#46;<span class="elsevierStyleSup">1&#44;3</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">miRNA Target Recognition and Function</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Once loaded into the RISC complex&#44; miRNAs recognize their target mRNAs by base-pair complementarity&#46; Target sequences are mainly located in the 3&#180; untranslated region &#40;UTR&#41; of mRNAs&#46; However&#44; functional miRNA binding sites can also be found in the 5&#180; UTR and open reading frame regions&#46;</p><p class="elsevierStylePara">Nucleotides in positions 2-8&#44; called seed sequence&#44; are essential for pairing with the target mRNA and miRNA function&#46; In the case of perfect complementarity of the seed sequence of the miRNA with the target sequence&#44; miRNAs act as a short interfering RNA &#40;siRNA&#41; promoting mRNA cleaving by RISC complex&#46; This mechanism is principally found in plants but is very rare in mammals&#46;</p><p class="elsevierStylePara">When pairing with target sequences is partially complementary&#44; which is the most frequent mechanism in mammals&#44; miRNA regulation is produced by mRNA translation repression or degradation&#46; However this degradation process is different and involves recruitment of deadenylase complexes that remove or shorten the poly-A tail of the target transcript&#46; Poly-A tail shortening induces decapping of the 5&#180; extreme of the transcript and uncapped mRNAs are rapidly degraded by 5&#180; to 3&#180; exoribonucleases &#40;Figure 1&#41;&#46;<span class="elsevierStyleSup">1&#44;3</span></p><p class="elsevierStylePara">Although the contribution rate of mRNA decay and translational repression to miRNA action is a controversial topic&#44; it seems clear that target degradation provides a major contribution to silencing in mammal cells&#46; In this regard&#44; it has been estimated that mRNA decay is present in 85&#37; of the miRNA regulation process whereas 15&#37; corresponds to translational repression&#46;<span class="elsevierStyleSup">3&#44;4</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">miRNA Decay and Turnover</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Accumulative evidence reveals that different miRNAs present distinct and inherent half-lives that could be encoded by their sequence or can be determined after maturation by post-transcriptional mechanisms such as uracile and adenosine addition to their 3&#180;end&#46;</p><p class="elsevierStylePara">Half-lives of some miRNAs could reach many hours or even days in some organs like the liver or the heart&#46;<span class="elsevierStyleSup">5&#44;6</span> However&#44; 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miRNA studies in kidney development and function have emerged as a field of intense research during the last few years&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">microRNAs in Normal Kidney Function and Development</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Several profiling studies have revealed microRNA profiles related to specific organs&#44; including the kidney&#46; These studies indicate that miR-146a&#44; miR-886&#44; miR-192&#44; miR-194&#44; miR-204&#44; miR-215 and miR-216 are renal-specific microRNAs&#46; In addition&#44; let-7a-g&#44; miR-196a&#47;b&#44; miR-10a&#47;b&#44; miR-130&#44; miR146&#44; miR-21&#44; miR-200a&#44; miR-30a-e and miR-872 are highly expressed in renal tissue&#46;<span class="elsevierStyleSup">8-11</span></p><p class="elsevierStylePara">microRNAs are essential for kidney development&#46; In fact&#44; lack of miRNA activity causes defects in kidney terminal differentiation such as decreased proliferation rate&#44; aberrant nephron patterning and delayed terminal differentiation of kidney tubules&#46; In this regard&#44; miR-30 and miR-200 family strictly regulate the temporal and spatial expression pattern of transcription factors involved in pro-nephron maturation&#46;<span class="elsevierStyleSup">12</span></p><p class="elsevierStylePara">Loss of microRNAs in nephron progenitors leads to early depletion of this cell population as renal growth progresses&#46; These effects are especially due to the regulation by miR-10a&#44; miR-106b and miR-17-5p of Bim&#44; a pro-apoptotic factor which increases its expression levels when miRNAs are depleted&#46;<span class="elsevierStyleSup">13</span></p><p class="elsevierStylePara">On the other hand&#44; some microRNAs have been related to kidney senescence&#46; Particularly&#44; overexpression of miR-335 and miR-34a in mesangial cells leads to premature senescence of this cell population by the regulation of mitochondrial antioxidative enzymes&#46;<span class="elsevierStyleSup">14</span></p><p class="elsevierStylePara">Studies based on DICER knockdown in podocytes&#44; juxtaglomerular cells and proximal tubules have unveiled the role of miRNAs in kidney function maintenance as well as specific miRNA roles in each kidney compartment&#46; KO of DICER in glomerulus results in progressive loss of podocyte function leading to proteinuria and kidney function impairment and ultimately leading to animal death&#46; Three microRNAs in particular have been identified as contributors to this renal failure &#40;miR-23b&#44; miR-24 and miR-26a&#41;&#46;<span class="elsevierStyleSup">13&#44;15</span> In addition&#44; Drosha ablation in podocytes results in proteinuric renal disease and collapsing glomerulopathy&#46;<span class="elsevierStyleSup">16</span></p><p class="elsevierStylePara">DICER deletion in juxtaglomerular cells produces acute loss of this cell type leading to an abrupt decrease of renin expression in kidney and deregulation of blood pressure&#46;<span class="elsevierStyleSup">17</span></p><p class="elsevierStylePara">Several microRNAs have also been unveiled as critical regulators of kidney function and homeostasis maintenance&#46; For instance&#44; miR-320a is a direct regulator of Aquoporin 1 and 4&#44; which are integral membrane transporters involved in water homeostasis&#46;<span class="elsevierStyleSup">18</span> Moreover&#44; the Na&#47;H exchange factor-1&#44; a regulator of ion transport in apical membrane&#44; is a target gene of miR-200b&#46;<span class="elsevierStyleSup">19</span></p><p class="elsevierStylePara">All these studies indicate that miRNAs play critical roles in normal renal function and physiology maintenance and when altered&#44; may lead to renal diseases&#46;&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">microRNAs in Kidney Disease</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Specific miRNAs deregulation has been linked to renal disease development&#46; For example&#44; miR-192 has been identified as a critical regulator of collagen production in diabetic nephropathy&#46;<span class="elsevierStyleSup">20</span> Studies in renal biopsies from diabetic patients have shown that miR-192 is poorly expressed in renal tissue&#46; This downregulation is directly correlated with tubulointerstitial fibrosis and low glomerular filtration rate &#40;GFR&#41; in diabetic patients&#46;<span class="elsevierStyleSup">21</span></p><p class="elsevierStylePara">Several microRNAs have been related to polycystic kidney disease &#40;PCK&#41;&#46; miR-10a&#44; miR30a-5p&#44; miR-96&#44; miR-126-5p&#44; miR-182&#44; miR-200a&#44; miR204&#44; miR-429 and miR-488 were downregulated in a Pkd1 -&#47;- mouse model&#46;<span class="elsevierStyleSup">22</span> Moreover&#44; miR-15 expression was decreased in a rat model of PCK&#46; Reduction of this microRNA increases the expression of Cdc25A&#44; a regulator of cell cycle&#44; promoting cyst growth&#46;<span class="elsevierStyleSup">23</span></p><p class="elsevierStylePara">microRNA deregulation has also been associated with renal carcinoma&#46; miRNA profiling experiments demonstrated that miR-28&#44; miR-185&#44; miR-7-2 and let-7f-2<span class="elsevierStyleSup">24</span> and miR-155&#44; miR-210&#44; miR-592&#44; miR-34b&#44; miR-224&#44; miR142-3p&#44; miR-185&#44; miR-34a&#44; and miR-21 were modulated in renal carcinoma tissue samples&#46;<span class="elsevierStyleSup">25 </span>All these microRNAs show target genes enriched in angiogenesis&#44; hypoxia&#44; apoptosis&#44; tumorogenesis&#44; invasion and metastasis pathways&#44; in agreement with the pathological context where they have described&#46;<span class="elsevierStyleSup">26</span></p><p class="elsevierStylePara">On the other hand&#44; the miR-200 family are repressors of E-cadherin during epithelial to mesenchimal transition &#40;EMT&#41;&#44; promoting cell migration and invasion during metastasis&#46;<span class="elsevierStyleSup">27&#44;28</span> In addition&#44; miR-200a and miR-141 are involved in EMT and fibrosis mediated by TGFb1 <span class="elsevierStyleItalic">in vivo</span> and <span class="elsevierStyleItalic">in vitro</span>&#44; and have an important implication in renal fibrosis development as demonstrated with animal experimental models&#46;<span class="elsevierStyleSup">29</span> These miRNAs could be considered as novel therapeutic target in EMT-associated nephropathies including chronic kidney diseases&#44; where efficient treatments are still not available&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">miRNAs in Renal Ischemia&#47;Reperfusion</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The clear role of miRNAs in kidney function and nephropathies and the ability of miRNAs to regulate rapid responses to stress and injury have unveiled microRNAs as potential key regulators of kidney responses to acute damage&#44; such as Acute Kidney Injury following renal Ischemia&#47;Reperfusion &#40;I&#47;R&#41;&#46;</p><p class="elsevierStylePara">miRNAs involvement in kidney response to I&#47;R was undoubtedly demonstrated by DICER KO experiments in proximal tubular cells&#46; DICER KO mice showed normal renal function and proximal tubule structure in basal conditions&#46; However&#44; general downregulation of miRNAs conferred a protection against I&#47;R injury&#44; since DICER KO animals subjected to I&#47;R exhibited significantly better renal function&#44; less tissue damage&#44; lower tubular apoptosis and improved survival compared to wild-type animals&#46;<span class="elsevierStyleSup">30</span></p><p class="elsevierStylePara">Global expression profiling experiments in mice undergoing renal I&#47;R have identified a signature of 9 microRNAs &#40;miR-21&#44; miR-20a&#44; miR-146a&#44; miR-199a-3p&#44; miR-214&#44; miR-192&#44; miR-187&#44; miR-805&#44; and miR-194&#41; which are differentially expressed in kidney compared to sham controls&#46;<span class="elsevierStyleSup">31</span> Moreover&#44; a more recent work from the same group demonstrates that microRNA signature after I&#47;R is different in operated animals when compared to sham controls and these differences are maintained and evolve along time&#46; Their data strongly evidence that altered miRNAs after I&#47;R could be considered as new biomarkers for renal I&#47;R injury&#46;<span class="elsevierStyleSup">32</span></p><p class="elsevierStylePara">In addition to the miRNAs signature of renal response to I&#47;R&#44; miRNAs also have been implicated in protection against ischemic injury&#44; showing that these molecules are potential novel therapeutic targets in this context&#46; In fact&#44; our lab recently demonstrated that miR-127 is a regulator of the proximal tubule cell response to I&#47;R injury&#46; Overexpression of this microRNA in an <span class="elsevierStyleItalic">in vitro</span> model of I&#47;R demonstrates that miR-127 prevents focal adhesion complex disassembly and thigh junction disruption provoked by I&#47;R&#46; Moreover&#44; kinesin familiy member 3B&#44; a component of the Kinesin II complex involved in intracellular vesicle trafficking&#44; is a target gene of miR-127 in proximal tubule cells during I&#47;R&#44; with important implications in kidney function&#46;<span class="elsevierStyleSup">33</span> Based on these results&#44; the potential role of miR-127 in the pathophysiology of ischemic proximal tubule injury is summarized in Figure 2&#46;</p><p class="elsevierStylePara">Moreover&#44; Liu F&#46; et al&#46; demonstrate that miR-210&#44; a well established miRNA regulated by hypoxia&#44; is involved in angiogenesis regulation during renal I&#47;R by activating VEGF and its receptor VEGFR2 expression&#44; contributing to ischemic injury recovery&#46;<span class="elsevierStyleSup">34</span> Regarding to vascular compartment involvement in renal I&#47;R response&#44; miRNAs contained in vesicles derived from endothelial progenitors protect renal cells from I&#47;R injury&#46; Intravenous injection of microvesicles confers functional and morphologic protection of renal cells by enhancing tubular cell proliferation and reducing apoptosis and leukocyte infiltration&#46; These miRNAs also protect kidney from chronic damage progression by inhibiting glomerulosclerosis and tubulointerstitial fibrosis&#46; Thus&#44; vesicle-derived miRNAs contribute to reprogram resident renal cells to a regenerative program after I&#47;R injury&#46;<span class="elsevierStyleSup">35</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">CIRCULATING microRNAs AS NOVEL BIOMARKERS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Even though the initial studies proposed that miRNAs were only present inside the cell&#44; 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serum miRNAs have demonstrated great stability and resistance to aggressive conditions such as RNAse treatment&#44; or drastic pH changes&#46;<span class="elsevierStyleSup">39</span> The mechanism underlying this unexpected miRNA stability in serum is still not completely understood&#44; but it has been evidenced that circulating microRNAs are released from cells in membrane vesicles which protects them from the environment&#46; Vesicles proposed to be carriers of circulating microRNAs include exosomes&#44; which are 50-90nm vesicles released by exocytosis from multivesicular bodies &#40;MVB&#41;<span class="elsevierStyleSup">36&#44;40</span> as well as larger microvesicles up to 1&#181;m&#46;<span class="elsevierStyleSup">41&#44;42</span> Furthermore&#44; recent studies have demonstrated that serum circulating miRNAs can also be carried by Argonaute2 proteins&#46;<span class="elsevierStyleSup">43</span></p><p class="elsevierStylePara">Taken together&#44; all these features demonstrate that serum circulating miRNAs achieve nearly all the required characteristics for an ideal biomarker&#46; Their presence in a peripheral fluid allows diagnosis by minimum invasive methods and samples can be easily and routinely obtained in clinical practice&#46; In addition to their high stability in fresh samples&#44; several studies have demonstrated that miRNAs maintain stability and reliability in long-term stored serum samples and in samples conserved at room temperature for hours&#46;<span class="elsevierStyleSup">39</span> Moreover&#44; they can be easily quantified by qRT-PCR&#44; with affordable technical effort&#46; These characteristics&#44; joined to their tissue and cell type specificity&#44; have revealed circulating miRNAs as promising biomarkers for more accurate diagnosis and monitoring of diseases&#46;</p><p class="elsevierStylePara">Regarding the advantage of circulating miRNAs as precise biomarkers in comparison to the ones available up to now&#44; it is important to notice that miRNAs could belong to the pathophysiological mechanisms responsible for diseases&#44; including renal diseases&#46; Therefore&#44; miRNAs could provide the clinician with critical additional information that is currently not accessible and they could also be considered as novel therapeutic targets&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">CIRCULATING microRNAs AS AKI BIOMARKERS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Despite the intense research in the circulating miRNAs field of the last years&#44; publications about their role as AKI biomarkers are still scarce&#46; However&#44; during the last two years some articles have started to point out this issue&#46;</p><p class="elsevierStylePara">Lorenzen JM et al&#46; in 2011 revealed that miR-210 was upregulated in plasma samples of a cohort of 77 AKI patients compared to healthy controls&#46; Moreover&#44; plasma levels of this microRNA could predict patient survival 4 weeks after initiation of Renal Replacement Therapy &#40;RRT&#41;&#46;<span class="elsevierStyleSup">44</span></p><p class="elsevierStylePara">In addition&#44; miR-21 and miR-155 are upregulated in renal tissue after I&#47;R or toxic injury&#44; correlating with a lower expression in blood and urinary supernatants&#46; Moreover&#44; these microRNAs were also modulated in urine samples of AKI patients compared to healthy volunteers&#46; Bioinformatics analysis of the target genes of these microRNAs evidenced that they were enriched in pathways related to apoptosis and cell proliferation&#46;<span class="elsevierStyleSup">45</span></p><p class="elsevierStylePara">A recent publication by Lan YF et al&#46;&#44; demonstrates that miR-494 is a regulator of the renal inflammatory response as well as apoptosis after I&#47;R injury&#46; Moreover&#44; detection of this miRNA in urine showed that miR-494 expression is 60 fold higher in AKI patients compared to healthy controls&#46;<span class="elsevierStyleSup">46</span></p><p class="elsevierStylePara">In addition to these reports&#44; our group has identified and validated a panel of 10 serum miRNAs&#44; including miR-101-1&#44; miR-127-3p&#44; miR-210&#44; miR-126&#44; miR-26b&#44; miR-29a&#44; miR-146a&#44; miR-27a&#44; miR-93&#42; and miR-10a&#44; as biomarkers of AKI&#44; using cohorts of intensive care units &#40;ICU&#41; patients with AKI and cardiac surgery with cardiopulmonary bypass patients&#46; ROC analysis for diagnostic value of the panel demonstrated sensitivity and specificity close to 100&#37;&#46; Moreover&#44; serum miRNAs detect AKI development before serum creatinine increases&#44; becoming early diagnostic tools&#46; These miRNAs provide additional valuable clinical information such as AKI severity&#44; AKI origin &#40;pre-renal or intrinsic&#41; or AKI aetiology&#46; Moreover&#44; serum miRNAs could be considered biomarkers of AKI predisposition since they can predict AKI development when when microRNA are estimated before cardiac surgery&#46;<span class="elsevierStyleSup">47</span></p><p class="elsevierStylePara">All these studies demonstrated that miRNAs could be precise biomarkers of AKI diagnosis useful in clinical practice&#44; offering valuable additional information in comparison with classical biomarkers&#46; Since miRNAs are capable of indicating survival&#44; recovery&#44; AKI origins or AKI aetiologies&#44; they could significantly contribute to improve AKI patient management&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">FUTURE PERSPECTIVES OF miRNAs IN AKI</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The information provided here identifies miRNAs as very promising molecules for increasing the knowledge of pathophysiological mechanisms underlying kidney diseases and very powerful tools for improving clinical management of renal patients&#46;</p><p class="elsevierStylePara">miRNAs identification and validation as biomarkers for nephropathies will contribute to more precise diagnostics and prognostics as well as will provide valuable additional information for patient handling&#46; Although it was not the main topic of this review&#44; miRNAs could also be considered as novel therapeutic targets in renal diseases&#46; In this regard&#44; the improved knowledge of miRNAs involved in renal I&#47;R injury and recovery could be a key point for developing new therapeutic approaches to prevent AKI&#44; reduce chronic renal disease derived from acute episodes and improve outcome&#46;</p><p class="elsevierStylePara">Identification of microRNAs as novel biomarkers for AKI could drastically change current clinical practice allowing earlier detection and better patient monitoring and handling&#46; Therefore&#44; taking into account the reported results and our findings&#44; the use of miRNAs in AKI clinical practice can be proposed&#44; based on the dynamic model of AKI by Pickering and Endre<span class="elsevierStyleSup">48</span> &#40;Figure 3&#41;&#46; This model establishes the concept of Phase-Specific AKI Biomarkers&#46;</p><p class="elsevierStylePara">miRNAs could be considered Phase-1 Biomarkers since they could identify patients in risk of AKI development&#44;<span class="elsevierStyleSup">47</span> thus allowing the application of preventive strategies&#46; miRNAs could also be Phase 2 Biomarkers since miRNAs expression correlates with AKI diagnosis before creatinine increases&#44; permitting the application of early therapeutic interventions&#46; Phase 3 Specific Biomarkers are able to monitor injury and repair&#46; In this regard&#44; serum miRNA levels correlate with severity and different recovery degrees&#46;<span class="elsevierStyleSup">45&#44;47</span> Finally&#44; Phase 4 Specific Biomarkers&#44; including serum miRNAs&#44; will identify AKI outcomes such as CKD development&#44; RRT requirement or survival&#46;<span class="elsevierStyleSup">44-47</span></p><p class="elsevierStylePara">In summary&#44; miRNAs have started to emerge as key players in many relevant diseases&#44; including nephropathies&#46; This review has aimed to introduce and overview miRNAs as exciting molecules in Experimental Nephrology and promising tools in Clinical Nephrology&#46;&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">KEY CONCEPTS</span></p><ul><li>microRNAs are small RNA molecules which are key regulators of gene expression&#46; </li><li>microRNAs are involved in normal kidney function and development as well as in development of renal pathologies&#46;</li><li>microRNAs can be detected in peripheral body fluids such as serum or urine&#46; </li><li>Circulating microRNAs detected in body fluids are novel biomarkers of renal diseases&#44; including Acute Kidney Injury&#46;</li></ul><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">FUNDING</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">This work was supported by grants<span class="elsevierStyleBold"> </span>FIS PS09&#47;02183 and PS12&#47;00094 by Instituto de Salud Carlos III &#40;ISCIII&#41; and Ayuda Intramural FIBIO HRYC 122&#47;2009&#46; EAF is supported by CAM-CIFRA &#40;S2010&#47;BMD-2378&#41;&#44; ER is funded by REDINREN &#40;RD12&#47;0021&#47;0020&#41;&#44; MR is recipient of contract from ISCIII &#40;CA11&#47;00491&#41;&#46; We are also grateful to F&#46; Jim&#233;nez for his valuable help with figures editing&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">The authors declare that they have no conflicts of interest related to the contents of this article&#46;</p><p class="elsevierStylePara"><a href="grande&#47;12198&#95;16025&#95;49916&#95;en&#95;f110&#46;12198&#95;i&#46;jpg" class="elsevierStyleCrossRefs"><img src="12198_16025_49916_en_f110.12198_i.jpg" alt="microRNA biogenesis&#44; function and secretion&#46; "></img></a></p><p class="elsevierStylePara">Figure 1&#46; microRNA biogenesis&#44; function and secretion&#46; </p><p class="elsevierStylePara"><a href="grande&#47;12198&#95;16025&#95;49918&#95;en&#95;f210&#46;12198&#95;i&#46;jpg" class="elsevierStyleCrossRefs"><img src="12198_16025_49918_en_f210.12198_i.jpg" alt="miR-127 as potential mediator of AKI pathophysiology in proximal tubule cells&#46;"></img></a></p><p class="elsevierStylePara">Figure 2&#46; miR-127 as potential mediator of AKI pathophysiology in proximal tubule cells&#46;</p><p class="elsevierStylePara"><a href="grande&#47;12198&#95;16025&#95;49919&#95;en&#95;f310&#46;12198&#95;i&#46;jpg" class="elsevierStyleCrossRefs"><img src="12198_16025_49919_en_f310.12198_i.jpg" alt="Circulating miRNAs as useful biomarkers of AKI in clinical practice&#46;"></img></a></p><p class="elsevierStylePara">Figure 3&#46; Circulating miRNAs as useful biomarkers of AKI in clinical practice&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara">Los microARN son peque&#241;as mol&#233;culas end&#243;genas de ARN de vital importancia para la regulaci&#243;n de la expresi&#243;n g&#233;nica&#46; Se han convertido en los mediadores biol&#243;gicos m&#225;s importantes que se han caracterizado en los &#250;ltimos diez a&#241;os&#46; Participan en casi todos los procesos celulares&#44; por lo que su desregulaci&#243;n est&#225; asociada al desarrollo de muchas patolog&#237;as&#44; entre las que se encuentran las renales&#46; Existen cada vez m&#225;s pruebas que demuestran que los microARN son reguladores claves de la funci&#243;n y el desarrollo renal&#44; aunque tambi&#233;n se encuentran en el origen de algunas enfermedades renales&#46; Los estudios m&#225;s recientes han concluido que estas mol&#233;culas pueden ser secretadas al exterior de la c&#233;lula&#44; lo que permite que puedan ser detectadas en fluidos perif&#233;ricos como la orina y el suero&#46; Adem&#225;s&#44; los microARN circulantes detectados en los fluidos corporales pueden ser biomarcadores adecuados de las enfermedades renales&#44; entre las que se incluye la lesi&#243;n renal aguda&#46; Esta nueva generaci&#243;n de biomarcadores renales podr&#237;a tener consecuencias importantes para la pr&#225;ctica cl&#237;nica&#44; ya que podr&#237;an contribuir significativamente a la mejora del manejo de los pacientes&#46; En este trabajo se revisa la implicaci&#243;n de los microARN en la homeostasis y la funci&#243;n renal y el papel de los microARN circulantes como nuevos biomarcadores de las enfermedades renales&#44; centr&#225;ndonos en su potencial utilidad para el manejo de la lesi&#243;n renal aguda&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara">microRNAs are small&#44; endogenous RNA molecules which are critical for a new step in the regulation of the gene expression&#46; They have become the most critical biological mediators characterized in the last ten years&#46; microRNAs participate in almost every cellular process&#44; therefore their deregulation is associated with the development of a wide range of pathologies&#44; including kidney diseases&#46; Increasing evidence demonstrates that microRNAs are key regulators of the normal kidney function and development&#44; but they are also at the basis of several renal diseases&#46; Recent works have established that these molecules can be secreted to extracellular environments&#44; enabling their detection in peripheral body fluids such as urine and serum&#46; Moreover&#44; circulating miRNAs detected in body fluids turn into suitable biomarkers of kidney diseases&#44; including acute kidney injury&#46; This new generation of renal biomarkers could have a great impact in the clinical practice&#44; significantly contributing to improve patient management&#46; In this review&#44; we discuss over the implication of microRNAs in normal kidney function and homeostasis as well as the role of circulating miRNAs as novel biomarkers of kidney diseases&#44; focusing on their potential usefulness in acute kidney injury management&#46;</p>"
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Article information

ISSN: 20132514
Original language: English

DOI:10.3265/Nefrologia.pre2013.Aug.12198

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2024 February	102	58	160
2024 January	69	28	97
2023 December	73	24	97
2023 November	73	31	104
2023 October	93	45	138
2023 September	108	37	145
2023 August	62	21	83
2023 July	95	30	125
2023 June	82	21	103
2023 May	82	37	119
2023 April	68	19	87
2023 March	84	24	108
2023 February	60	18	78
2023 January	72	33	105
2022 December	82	39	121
2022 November	91	38	129
2022 October	105	36	141
2022 September	74	32	106
2022 August	82	59	141
2022 July	86	55	141
2022 June	105	45	150
2022 May	89	45	134
2022 April	119	54	173
2022 March	122	63	185
2022 February	111	56	167
2022 January	117	49	166
2021 December	117	46	163
2021 November	96	45	141
2021 October	93	47	140
2021 September	84	38	122
2021 August	128	64	192
2021 July	93	40	133
2021 June	77	47	124
2021 May	95	40	135
2021 April	182	77	259
2021 March	120	64	184
2021 February	132	47	179
2021 January	87	47	134
2020 December	78	40	118
2020 November	79	30	109
2020 October	68	26	94
2020 September	92	25	117
2020 August	79	32	111
2020 July	95	32	127
2020 June	122	29	151
2020 May	146	40	186
2020 April	111	39	150
2020 March	87	34	121
2020 February	70	30	100
2020 January	95	42	137
2019 December	103	31	134
2019 November	62	35	97
2019 October	76	19	95
2019 September	86	48	134
2019 August	47	37	84
2019 July	66	28	94
2019 June	57	21	78
2019 May	61	28	89
2019 April	123	42	165
2019 March	91	35	126
2019 February	39	23	62
2019 January	54	44	98
2018 December	126	48	174
2018 November	145	21	166
2018 October	174	25	199
2018 September	323	23	346
2018 August	140	16	156
2018 July	148	21	169
2018 June	117	15	132
2018 May	176	20	196
2018 April	126	11	137
2018 March	131	19	150
2018 February	111	9	120
2018 January	100	15	115
2017 December	109	12	121
2017 November	120	20	140
2017 October	72	11	83
2017 September	135	11	146
2017 August	145	27	172
2017 July	176	11	187
2017 June	168	20	188
2017 May	171	22	193
2017 April	112	14	126
2017 March	136	17	153
2017 February	267	21	288
2017 January	103	17	120
2016 December	164	15	179
2016 November	248	22	270
2016 October	294	20	314
2016 September	454	23	477
2016 August	536	34	570
2016 July	373	126	499
2016 June	242	0	242
2016 May	222	0	222
2016 April	201	0	201
2016 March	204	0	204
2016 February	212	0	212
2016 January	209	0	209
2015 December	198	0	198
2015 November	167	0	167
2015 October	187	0	187
2015 September	135	0	135
2015 August	134	0	134
2015 July	203	0	203
2015 June	133	0	133
2015 May	137	0	137
2015 April	14	0	14

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