Información de la revista
Vol. 34. Núm. 6.Noviembre 2014
Páginas 693-810
Vol. 34. Núm. 6.Noviembre 2014
Páginas 693-810
Acceso a texto completo
Efecto protector de la adrenomedulina en la nefropatía inducida por contraste en ratas
Protective effect of adrenomedullin on contrast induced nephropathy in rats
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Salih Inala, Eyüp Kocb, Gülay Ulusal-Okyayc, Özge T. Pasaoglud, Ipek Isik-Gönüle, Eser Öz-Oyarf, Hatice Pasaoglud, Galip Güza
a Department of Nephrology, Gazi University Faculty of Medicine, Ankara, Turkey,
b Department of Nephrology, Kirikkale University Faculty of Medicine, Kirikkale, Turkey,
c Department of Nephrology, Gazi University Faculty of Medicine, Ankara, Turkey,
d Department of Biochemistry, Gazi University Faculty of Medicine, Ankara, Turkey,
e Department of Pathology, Gazi University Faculty of Medicine, Ankara, Turkey,
f Department of Physiology, Gazi University Faculty of Medicine, Ankara, Turkey,
Este artículo ha recibido
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Antecedentes y objetivos: La incidencia de la nefropatía inducida por contraste (NIC) está aumentando y la vasoconstricción renal y la hipoxia medular son mecanismos importantes. Los enfoques terapéuticos son muy limitados y existe un gran interés en avanzar en las estrategias preventivas. La adrenomedulina es un péptido relativamente nuevo con propiedades antioxidantes, vasoactivas y vasodilatadoras. Nuestro objetivo es investigar si la adrenomedulina puede jugar un papel preventivo frente al desarrollo de la NIC experimental. Métodos: Se distribuyeron ratas Wistar albinas (n = 24) de forma aleatoria en cuatro grupos de 6: control (C), adrenomedulina (A), medio de contraste (MC) y adrenomedulina más medio de contraste (AMC). Las ratas no ingirieron agua desde el día 1 al día 4 (durante 72 horas). Posteriormente, se les administraron las sustancias de forma intravenosa. Los grupos A y AMC recibieron una dosis de adrenomedulina de 12 µg/kg. Los grupos MC y AMC recibieron una única dosis de medio de contraste de alta osmolaridad: 10 ml/kg de diatrizoato (Urografin 76 %, Schering AG, Alemania). Los días 1 y 6 se tomaron muestras de sangre para realizar análisis de función renal y de marcadores inflamatorios, incluidos el TNF-α, IL-1β, IL-6 e IL-18. Tras el sacrificio, se examinaron las histologías renales con tinción hematoxilina-eosina. Resultados: En comparación con el grupo MC, los niveles de cistatina C sérica fueron significativamente inferiores en el grupo AMC (< 0,05). Además, la tasa de excreción diaria de proteínas, los cambios absolutos en el gasto urinario diario y los valores de aclaramiento de la creatinina fueron significativamente inferiores en el grupo AMC que en el grupo MC (< 0,05). En la evaluación histopatológica, en lo que respecta al grado de daño tubular y los valores de congestión medular, el grupo AMC presentaba niveles ligeramente mejores en comparación con el grupo MC. Sin embargo, según los marcadores inflamatorios, las diferencias no presentaron significación estadística. Conclusión: El estudio ha demostrado que la adrenomedulina resulta beneficiosa en los análisis de función renal deteriorada en un modelo experimental de NIC. Por lo tanto, la adrenomedulina puede ser un candidato para la profilaxis de la NIC. No obstante, se necesitan más estudios que arrojen luz sobre este tema.

Palabras clave:
Modelo de rata
Palabras clave:
Medio de radiocontraste
Palabras clave:
Nefropatía inducida por contraste
Palabras clave:
Adrenomedulina

Background and aims: Contrast-induced nephropathy (CIN) has a growing incidence in which renal vasoconstriction and medullary hypoxia are important mechanisms. Therapeutic approaches are very restricted and there is a considerable interest in advancing preventive strategies. Adrenomedullin is a relatively novel peptide having antioxidant, vasoactive and vasodilatory properties. We aimed to investigate whether adrenomedullin might have a preventive role against the development of experimental CIN. Methods: Wistar albino rats (n=24) were allocated randomly into four equal groups of 6 each; Control (C), Adrenomedullin (A), Contrast Media (CM) and Adrenomedullin plus Contrast Media (ACM). All rats were deprived of water from day 1 to day 4 during 72 hours. Then, intravenous administrations of chemicals were performed. Adrenomedullin was given at dose of 12µg/kg to groups A and ACM. A single dose of high-osmolar contrast media; diatrizoate (Urografin 76%, Schering AG, Germany) was injected to groups CM and ACM at dose of 10mL/kg. On day 1 and 6 blood samples were drawn for renal function tests and inflammatory markers including TNF-α IL-1β, IL-6 and IL-18. After sacrification, kidney histologies were examined with hematoxylin-eosin staining. Results: Compared to CM group, serum cystatin-C levels on 6th day were found significantly lower in ACM group (p<0.05). Additionally, daily protein excretion rates, absolute changes in daily urine output and creatinine clearance values were significantly lower in ACM group than those in CM group (p<0.05). In histopathological evaluation, regarding the degree of tubular damage and medullary congestion scores, ACM group had slightly better scores compared to CM group; however the differences did not reach significance as shown in inflammatory markers. Conclusion: This study demonstrated a beneficial impact of adrenomedullin on deteriorated renal function tests in an experimental CIN model. Adrenomedullin might be a candidate agent for prophylaxis of CIN. However, further studies are needed to shed more light on this issue.

Keywords:
Rat model
Keywords:
Radiocontrast media
Keywords:
Contrast-induced nephropathy
Keywords:
Adrenomedullin
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Bibliografía
[1]
Shiragami K, Fujii Z, Sakumura T, Shibuya M, Takahashi N, Yano M, et al. Effect of a contrast agent on long-term renal function and the efficacy of prophylactic hemodiafiltration. Circ J 2008;72:427-33. [Pubmed]
[2]
McCullough PA, Soman SS. Contrast-induced nephropathy. Crit Care Clin 2005;21:261-80. [Pubmed]
[3]
Weisbord SD, Palevsky PM. Contrast-induced acute kidney injury: short- and long-term implications. Semin Nephrol 2011;31:300-9. [Pubmed]
[4]
Pannu N, Wiebe N, Tonelli M; Alberta Kidney Disease Network. Prophylaxis strategies for contrast-induced nephropathy. JAMA 2006;295:2765-79. [Pubmed]
[5]
Detrenis S, Meschi M, Musini S, Savazzi G. Lights and shadows on the pathogenesis of contrast-induced nephropathy: state of the art. Nephrol Dial Transplant 2005;20:1542-50. [Pubmed]
[6]
Agmon Y, Peleg H, Greenfeld Z, Rosen S, Brezis M. Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. J Clin Invest 1994;94:1069-75. [Pubmed]
[7]
Myers SI, Wang L, Liu F, Bartula LL. Iodinated contrast induced renal vasoconstriction is due in part to the downregulation of renal cortical and medullary nitric oxide synthesis. J Vasc Surg 2006;44:383-91. [Pubmed]
[8]
Van Praet JT, De Vriese AS. Prevention of contrast-induced nephropathy: a critical review. Curr Opin Nephrol Hypertens 2007;16:336-47. [Pubmed]
[9]
Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993;192:553-60. [Pubmed]
[10]
Pearson LJ, Rait C, Nicholls MG, Yandle TG, Evans JJ. Regulation of adrenomedullin release from human endothelial cells by sex steroids and angiotensin-II. J Endocrinol 2006;191:171-7. [Pubmed]
[11]
Yang S, Zhou M, Fowler DE, Wang P. Mechanisms of the beneficial effect of adrenomedullin and adrenomedullin-binding protein-1 in sepsis: down-regulation of proinflammatory cytokines. Crit Care Med 2002;30:2729-35. [Pubmed]
[12]
Wu R, Zhou M, Wang P. Adrenomedullin and adrenomedullin binding protein-1 downregulate TNF-alpha in macrophage cell line and rat Kupffer cells. Regul Pept 2003;112:19-26. [Pubmed]
[13]
Hinson JP, Kapas S, Smith DM. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev 2000;21:138-67. [Pubmed]
[14]
Shah KG, Rajan D, Jacob A, Wu R, Krishnasastry K, Nicastro J, et al. Attenuation of renal ischemia and reperfusion injury by human adrenomedullin and its binding protein. J Surg Res 2010;163:110-7. [Pubmed]
[15]
Wu R, Dong W, Qiang X, Ji Y, Cui T, Yang J, et al. Human vasoactive hormone adrenomedullin and its binding protein rescue experimental animals from shock. Peptides 2008;29:1223-30. [Pubmed]
[16]
Zhang F, Wu R, Zhou M, Blau SA, Wang P. Human adrenomedullin combined with human adrenomedullin binding protein-1 is protective in gut ischemia and reperfusion injury in the rat. Regul Pept 2009;152:82-7. [Pubmed]
[17]
Bartorelli AL, Marenzi G. Contrast-induced nephropathy. J Interv Cardiol 2008;21:74-85. [Pubmed]
[18]
Kagan A, Sheikh-Hamad D. Contrast-induced kidney injury: focus on modifiable risk factors and prophylactic strategies. Clin Cardiol 2010;33:62-6. [Pubmed]
[19]
Hiragushi K, Wada J, Eguchi J, Matsuoka T, Yasuhara A, Hashimoto I, et al. The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats. Kidney Int 2004;65:540-50. [Pubmed]
[20]
Samson WK. Adrenomedullin and the control of fluid and electrolyte homeostasis. Annu Rev Physiol 1999;61:363-89. [Pubmed]
[21]
Mukoyama M, Sugawara A, Nagae T, Mori K, Murabe H, Itoh H, et al. Role of adrenomedullin and its receptor system in renal pathophysiology. Peptides 2001;22:1925-31. [Pubmed]
[22]
Liu X, Zhang Z, Zhang X, Zhu H, Chen Q, Guo M. The localization of adrenomedullin in rat kidney tissue and its inhibitory effect on the growth of cultured rat mesangial cells. Chin Med Sci J 2002;17:129-33. [Pubmed]
[23]
Uetake R, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Iesato Y, et al. Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection. PLoS One 2014;9:e87667. [Pubmed]
[24]
Wang Y, Li R, Qiao X, Tian J, Su X, Wu R, et al. Intermedin/adrenomedullin 2 protects against tubular cell hypoxia-reoxygenation injury in vitro by promoting cell proliferation and upregulating cyclin D1 expression. Nephrology (Carlton) 2013;18:623-32.
[25]
Herget-Rosenthal S, Marggraf G, Hüsing J, Göring F, Pietruck F, Janssen O, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004;66:1115-22. [Pubmed]
[26]
Schrier RW, Wang W, Poole B, Mitra A. Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 2004;114:5-14. [Pubmed]
[27]
Hayashi M, Tojo A, Shimosawa T, Fujita T. The role of adrenomedullin in the renal NADPH oxidase and (pro)renin in diabetic mice. J Diabetes Res 2013;2013:134395.
[28]
Chini EN, Chini CC, Bolliger C, Jougasaki M, Grande JP, Burnett JC Jr, et al. Cytoprotective effects of adrenomedullin in glomerular cell injury: central role of cAMP signaling pathway. Kidney Int 1997;52:917-25. [Pubmed]
[29]
Kubo A, Minamino N, Isumi Y, Katafuchi T, Kangawa K, Dohi K, et al. Production of adrenomedullin in macrophage cell line and peritoneal macrophage. J Biol Chem 1998;273:16730-8. [Pubmed]
[30]
Kamoi H, Kanazawa H, Hirata K, Kurihara N, Yano Y, Otani S. Adrenomedullin inhibits the secretion of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, from rat alveolar macrophages. Biochem Biophys Res Commun 1995;211:1031-5. [Pubmed]
[31]
Itoh Y, Yano T, Sendo T, Oishi R. Clinical and experimental evidence for prevention of acute renal failure induced by radiographic contrast media. J Pharmacol Sci 2005;97:473-88. [Pubmed]
[32]
Persson PB, Hansell P, Liss P. Pathophysiology of contrast medium-induced nephropathy. Kidney Int 2005;68:14-22. [Pubmed]
[33]
Parvez Z, Rahman MA, Moncada R. Contrast media-induced lipid peroxidation in the rat kidney. Invest Radiol 1989;24:697-702. [Pubmed]
[34]
Deray G, Baumelou B, Martinez F, Brillet G, Jacobs C. Renal vasoconstriction after low and high osmolar contrast agents in ischemic and non-ischemic canine kidney. Clin Nephrol 1991;36:93-6. [Pubmed]
[35]
Toprak O, Cirit M. Risk factors for contrast-induced nephropathy. Kidney Blood Press Res 2006;29:84-93. [Pubmed]
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