NDT Advance Access originally published online on February 2, 2009
Nephrology Dialysis Transplantation 2009 24(8):2378-2383; doi:10.1093/ndt/gfp012
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Fluvastatin prevents podocyte injury in a murine model of HIV-associated nephropathy
1 Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan 2 Kidney Disease Section, NIDDK, NIH, Bethesda, MD, USA
Correspondence and offprint requests to: Takashi Kuroiwa; E-mail: tkuroiwa{at}med.gunma-u.ac.jp
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Abstract |
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Background. Recent studies have reported that statins have renoprotective effects, independent from lowering plasma cholesterol. In this study, we examined whether statins were beneficial in a murine model of HIV-associated nephropathy (HIVAN).
Methods. We used conditional transgenic mice that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and the Tet-on system. These mice develop aggressive collapsing focal segmental glomerular sclerosis with massive proteinuria and deterioration of renal function within 4 weeks following heminephrectomy and doxycycline administration. Fluvastatin was administrated simultaneously with doxycycline, and the effect was compared with untreated controls after 4 weeks.
Results. Fluvastatin at 10 mg/kg/day significantly decreased urinary albumin excretion (87 versus 11 mg/day, P < 0.01) and glomerular sclerosis (2.4 versus 1.0, P < 0.01, assessed by semi-quantitative scoring: 0–4). Fluvastatin also decreased serum creatinine and total cholesterol, but these differences were not statistically significant (0.36 versus 0.32 mg/dl, P = 0.35; 492 versus 378 mg/dl, P = 0.11, respectively). Phenotypic changes in podocytes, as indicated by the downregulation of nephrin, Wilms’ tumour 1 and synaptopodin, along with upregulation of proliferating cell nuclear antigen, were attenuated by fluvastatin, suggesting its protective effects against podocyte injuries. In cultured podocytes, angiotensin II treatment decreased nephrin expression to 13% of basal levels, which was reversed to 58% by adding fluvastatin.
Conclusions. In conclusion, fluvastatin was effective in treating experimental HIVAN. The beneficial effect of this drug might be caused, in part, by preserving nephrin expression in podocytes against angiotensin II-mediated injury.
Keywords: fluvastatin; HIV-associated nephropathy; podocyte
Received for publication: 8. 9.08
Accepted in revised form: 6. 1.09