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1 Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of; Nephrology and Dialysis Unit, Department of Internal Medicine, Affiliated Hospital, YanBian University Medical College, YanJi, China
2 Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of; Cell Death Disease Research Center, The Catholic University of Korea, Seoul, Korea, Republic of
3 Department of Anatomy, The Catholic University of Korea, Seoul, Korea, Republic of; Cell Death Disease Research Center, The Catholic University of Korea, Seoul, Korea, Republic of
4 Department of Internal Medicine, College of Medicine, University of Ulsan, Seoul, Korea, Republic of
5 Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of
* To whom correspondence should be addressed. E-mail: yanch{at}catholic.ac.kr.
We investigated the effects of pravastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, on interstitial inflammation and fibrosis,
using an animal model of chronic cyclosporine (CsA)-induced nephropathy. Sprague-Dawley rats were maintained on a low-salt diet (0.05% sodium) and treated daily for 1 or 4
weeks with vehicle (olive oil, 1 mL/kg s.c), CsA (15 mg/kg s.c), or both CsA and pravastatin(5 or 20 mg/kg in drinking water). Anti-inflammatory and anti-fibrotic effects of pravastatin were studied by evaluating the concentrations of the inflammatory mediators osteopontin(OPN) and C-reactive protein (CRP), of fibrotic cytokine-transforming growth factor (TGF)-
1, and the presence of ED-1-positive cells (macrophages). In addition, renal function,
serum lipid levels, histopathology (arteriolopathy and tubulointerstitial fibrosis), and the expression of the vasoactive factors endothelial nitric oxide synthase (eNOS) and renin protein were also compared for different treatment groups. Pravastatin induced dosedependent decreases in the expression of OPN, intrarenal CRP, and TGF-1, and in the numbers of ED-1-positive cells at 1 and 4 weeks. These were accompanied by a significant attenuation of tubulointerstitial fibrosis at 4 weeks. The downregulation of eNOS protein expression in CsA-treated rat kidney was markedly upregulated by pravastatin
treatment, although intrarenal renin expression was unaffected. Renal dysfunction induced by CsA significantly improved with administration of pravastatin at a dose of 20 mg/kg. Neither CsA nor pravastatin influenced serum lipid or hs-CRP levels in the treatment groups. Thus, in chronic CsA nephropathy, pravastatin effectively abrogates the
progression of tubulointerstitial inflammation and fibrosis. This may support the clinical use of pravastatin.
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