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 Charite ´, Humboldt University of Berlin, Berlin, Germany; and § Division of Nephrology, Department of Medicine, Rheinisch-Westfa ¨lische Technische Hochschule (RWTH) Aachen, Aachen, Germany. 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 inflam- matory cytokine production. Hydroxy-3-methylglutaryl coen- zyme A reductase inhibitors (“statins”) directly influence in- flammatory mechanisms. The hypothesis that ischemia- induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were ana- lyzed 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). Simulta- neously, ischemia-induced severe decreases in GFR were sig- nificantly 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 detach- ment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infil- tration 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 ob- served 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-methyl- glutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus re- duces 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. Renal ischemia-reperfusion injury is a major cause of acute renal failure (ARF) after major surgery or renal transplantation (1,2). Several experimental ameliorative strategies have been tested (3). However, there is still a remarkable lack of defini- tive evidence supporting specific prophylactic therapies in any setting (4). Postischemic ARF seems to be a consequence of hypoxia attributable to impaired perfusion, with subsequent reperfusion leading to acute inflammatory changes. Pathophys- iologic mechanisms include intracellular damage, with ATP depletion (5), and intracellular Ca 2+ accumulation (6). Cellular activation leads to reactive oxygen species generation, phos- pholipase activation, and membrane lipid alterations (7). In- flammatory reactions are characterized by surface adhesion molecule expression, followed by leukocyte infiltration, pro- tease activation, and cytokine production (8). Reorganization of integrins from basal to apical surfaces of injured tubular epithelial cells has been demonstrated to facilitate detachment, contributing to tubular obstruction (9). These changes are most pronounced in the outer medullary stripe, i.e., a part of the kidney that is extremely susceptible to hypoperfusion and hypoxic damage (10). Other compartments, such as the corti- comedullary junction, are also injured, however. We and others have demonstrated that inhibition of inflammatory pathways, such as inhibition of redox-sensitive nuclear factor-B (NF- B) or blockade of intercellular adhesion molecule-1 Received August 28, 2001. Accepted May 14, 2002. 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@mh-hannover.de 1046-6673/1309-2288 Journal of the American Society of Nephrology Copyright © 2002 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000026609.45827.3D J Am Soc Nephrol 13: 2288–2298, 2002