2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gueler, F. Articles by Haller, H. Search for Related Content PubMed PubMed Citation Articles by Gueler, F. Articles by Haller, H.

Postischemic Acute Renal Failure Is Reduced by Short-Term Statin Treatment in a Rat Model

Faikah Gueler^*, Song Rong^*, Joon-Keun Park^*, Anette Fiebeler^*, Jan Menne, Marlies Elger^*, Dominik N. Mueller, Franziska Hampich, Ralf Dechend, Uta Kunter, Friedrich C. Luft and Hermann Haller^*

*Department of Internal Medicine-Nephrology, Hannover Medical School, Hannover, Germany; Phenomiques GmbH, Hannover, Germany; Franz Volhard Clinic HELIOS Klinikum-Berlin, Max Delbrueck Center of Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany; and Division of Nephrology, Department of Medicine, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.

Correspondence to Dr. Hermann Haller, Department of Nephrology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Phone: 49-511-6319; Fax: 49-511-552366; E-mail: haller.hermann{at}mh-hannover.de

ABSTRACT. Postischemic acute renal failure (ARF) is common and often fatal. Cellular mechanisms include cell adhesion, cell infiltration and generation of oxygen free radicals, and inflammatory cytokine production. Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") directly influence inflammatory mechanisms. The hypothesis that ischemia-induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were analyzed in a uninephrectomized rat model. Male Sprague-Dawley rats were pretreated with cerivastatin (0.5 mg/kg) or vehicle for 3 d. Ischemic ARF was induced by left renal artery clipping for 45 min, while the right kidney was being removed. After 24 h of ARF, serum creatinine levels were increased 7.5-fold in vehicle-treated control animals with ARF, compared with sham-operated animals (P < 0.005). Statin treatment reduced the creatinine level elevation by 40% (P < 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 ± 0.09 ml/min, n = 13; ischemia without treatment, 0.06 ± 0.02 ml/min, n = 9; ischemia with statin pretreatment, 0.21 ± 0.03 ml/min, n = 11; P < 0.001). Furthermore, statin pretreatment prevented the occurrence of tubular necrosis, with marked loss of the brush border, tubular epithelial cell detachment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infiltration was almost completely prevented, intercellular adhesion molecule-1 upregulation was greatly decreased, and inducible nitric oxide synthase expression was reduced. Fibronectin and collagen IV expression was reduced, approaching levels observed in sham-operated animals. In vehicle-treated rats with ARF, mitogen-activated protein kinase extracellular activated kinase-1/2 activity was increased and the transcription factors nuclear factor-B and activator protein-1 were activated. Statin treatment reduced this activation toward levels observed in sham-operated rats. The data suggest that hydroxy-3-methylglutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus reduces the severity of ARF. The chain of events may involve anti-inflammatory effects, with inhibition of mitogen-activated protein kinase activation and the redox-sensitive transcription factors nuclear factor-B and activator protein-1.

This article has been cited by other articles:

				F. Gueler, S. Rong, W. Gwinner, M. Mengel, V. Brocker, S. Schon, T. F. Greten, H. Hawlisch, T. Polakowski, K. Schnatbaum, et al. Complement 5a Receptor Inhibition Improves Renal Allograft Survival J. Am. Soc. Nephrol., December 1, 2008; 19(12): 2302 - 2312. [Abstract] [Full Text] [PDF]

				R. Yin, J. Zhu, Z. Wang, H. Huang, J. Qian, Z. Li, and H. Jing Simvastatin attenuates cardiac isograft ischemia-reperfusion injury by down-regulating CC chemokine receptor-2 expression J. Thorac. Cardiovasc. Surg., September 1, 2007; 134(3): 780 - 788. [Abstract] [Full Text] [PDF]

				F. Gueler, J.-K. Park, S. Rong, T. Kirsch, C. Lindschau, W. Zheng, M. Elger, A. Fiebeler, D. Fliser, F. C. Luft, et al. Statins Attenuate Ischemia-Reperfusion Injury by Inducing Heme Oxygenase-1 in Infiltrating Macrophages Am. J. Pathol., April 1, 2007; 170(4): 1192 - 1199. [Abstract] [Full Text] [PDF]

				A. R. Chade, X. Zhu, O. P. Mushin, C. Napoli, A. Lerman, and L. O. Lerman Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia FASEB J, August 1, 2006; 20(10): 1706 - 1708. [Abstract] [Full Text] [PDF]

				P. Devarajan Update on Mechanisms of Ischemic Acute Kidney Injury J. Am. Soc. Nephrol., June 1, 2006; 17(6): 1503 - 1520. [Full Text] [PDF]

				S. Shibata, M. Nagase, and T. Fujita Fluvastatin Ameliorates Podocyte Injury in Proteinuric Rats via Modulation of Excessive Rho Signaling J. Am. Soc. Nephrol., March 1, 2006; 17(3): 754 - 764. [Abstract] [Full Text] [PDF]

				M. Tonelli, C. Isles, T. Craven, A. Tonkin, M. A. Pfeffer, J. Shepherd, F. M. Sacks, C. Furberg, S. M. Cobbe, J. Simes, et al. Effect of Pravastatin on Rate of Kidney Function Loss in People With or at Risk for Coronary Disease Circulation, July 12, 2005; 112(2): 171 - 178. [Abstract] [Full Text] [PDF]

				M. S. Goligorsky Whispers and shouts in the pathogenesis of acute renal ischaemia Nephrol. Dial. Transplant., February 1, 2005; 20(2): 261 - 266. [Full Text] [PDF]

				S. Miyahara, J. Kiryu, K. Yamashiro, K. Miyamoto, F. Hirose, H. Tamura, H. Katsuta, K. Nishijima, A. Tsujikawa, and Y. Honda Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes Am. J. Pathol., May 1, 2004; 164(5): 1697 - 1706. [Abstract] [Full Text] [PDF]

				M. Sabbatini, A. Pisani, F. Uccello, V. Serio, R. Seru, R. Paterno, B. Cianciaruso, G. Fuiano, and M. Andreucci Atorvastatin Improves the Course of Ischemic Acute Renal Failure in Aging Rats J. Am. Soc. Nephrol., April 1, 2004; 15(4): 901 - 909. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673