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

Abstract

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 ischemiainduced 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 Ͻ 0.005). Statin treatment reduced the creatinine level elevation by 40% (P Ͻ 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 Ϯ 0.09 ml/min, n ϭ 13; ischemia without treatment, 0.06 Ϯ 0.02 ml/min, n ϭ 9; ischemia with statin pretreatment, 0.21 Ϯ 0.03 ml/min, n ϭ 11; P Ͻ 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.

Endothelial Krüppel-Like Factor 4 Mediates the Protective Effect of Statins against Ischemic AKI

“…On the third day, both mice were subjected to bilateral renal I/R injury. Consistent with the results of previous studies, 14,15 treatment with fluvastatin ameliorated renal I/R injury in control mice, as assessed by serum levels of urea nitrogen and creatinine, histologic analyses, and expression of cell adhesion molecules ( Figure 6). However, of importance, fluvastatin did not attenuate renal I/R injury in Klf4 cKO mice.…”

“…To address this question, we derived conditional Klf4-deficient mice in ECs (Klf4 cKO mice) by breeding Tek-Cre mice 12 with mice carrying a loxP allele of Klf4 (Klf4 loxP mice) 13 and analyzed their phenotype after bilateral renal ischemia. In addition, statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been shown to improve ischemic AKI in rodents 14,15 and humans. 16,17 For example, pretreatment with cerivastatin for 3 days reduced renal I/R injury by preventing inflammatory cell infiltration and by inhibiting Icam1 induction.…”

“…16,17 For example, pretreatment with cerivastatin for 3 days reduced renal I/R injury by preventing inflammatory cell infiltration and by inhibiting Icam1 induction. 14 Therefore, we also examined whether endothelial Klf4 mediated the protective effect of statins against renal I/R injury.…”

Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes

“…[33][34][35][36][47][48][49] These differences may derive from the diversity of the mechanisms of each model or duration of the drug administration. In addition, many studies with streptozotocin-induced diabetic animals were performed for a relatively short duration compared to chronic diabetes in human.…”

Peri-surgical Statins Lessen Acute Kidney Injury

“…3,4 Only recently have studies demonstrated the significance of FGF23 in mineral metabolism in the larger population of patients with CKD and ESRD. [5][6][7] In 2007, Fliser et al 8 reported that higher FGF23 levels were strongly associated with progression of non diabetic CKD. The next year, Gutierrez et al 9 published that incident hemodialysis patients with higher FGF23 levels were at substantially greater risk for allcause mortality.…”