Cerivastatin prevents angiotensin II-induced renal injury independent of blood pressure- and cholesterol-lowering effects

Background. Statins are effective in prevention of endorgan damage; however , the benefits cannot be fully explained on the basis of cholesterol reduct ion. We used an angiotensin II (Ang II)-dependent model to test the hypothe sis that cerivastatin prevents leukocyte adhesion and infiltration, inducti on of inducible nitric oxide synthase (iNOS), and ameliorates endorgan dama ge. Methods. We analyzed intracellular targets, such as mitogen activated prote in kinase and transcription factor (nuclear factor-kappa B and activator pr otein-1) activation. We used immunohistochemistry, immunocytochemistry, ele ctrophoretic mobility shift assays, and enzyme-linked immunosorbent assay t echniques. We treated rats transgenic for human renin and angiotensinogen ( dTGR) chronically from week 4 to 7 with cerivastatin (0.5 mg/kg by gavage). Results. Untreated dTGR developed hypertension, cardiac hypertrophy, and re nal damage, with a 100-fold increased albuminuria and focal cortical necros is. dTGR mortality at the age of seven weeks was 45%. Immunohistochemistry showed increased iNOS expression in the endothelium and media of small vess els, infiltrating cells. afferent arterioles, and glomeruli of dTGR, which was greater in cortex than medulla. Phosphorylated extracellular signal reg ulated kinase (p-ERK) was increased in dTGR: nuclear factor-kappa B and act ivator protein-1 were both activated. Cerivastatin decreased systolic blood pressure compared with untreated dTGR (147 +/- 14 vs. 201 +/- 6 mm Hg, P < 0.001). Albuminuria was reduced by 60% (P = 0.001), and creatinine was low ered (0.45 +/- 0.01 vs. 0.68 +/- 0.05 mg/dL, P = 0.003); however, cholester ol was not reduced. Intercellular adhesion molecule-1 and vascular cell adh esion molecule-1 expression was diminished, while neutrophil and monocyte i nfiltration in the kidney was markedly reduced. ERK phosphorylation and tra nscription factor activation were reduced. In addition, in vitro incubation of vascular smooth muscle cells with cerivastatin (0.5 mu mol/L) almost co mpletely prevented the Ang II-induced ERK phosphorylation. Conclusion. Cerivastatin reduced inflammation, cell proliferation, and iNOS induction, which led to a reduction in cellular damage. Our findings sugge st that 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase inhibition ameliorates Ang II-induced end-organ damage. We suggest that these effects were independent of cholesterol.