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NDT Advance Access published online on April 26, 2005
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfh859
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received October 22, 2004
Accepted April 6, 2005

Original Articles

Simvastatin attenuates renal inflammation, tubular transdifferentiation and interstitial fibrosis in rats with unilateral ureteral obstruction

José Mauro Vieira Jr1*, Eduardo Mantovani 1, Leonardo Tavares Rodrigues 1, Humberto Dellê 1, Irene Lourdes Noronha 1, Clarice Kazue Fujihara 1, and Roberto Zatz 1

1 Internal Medicine, Renal Division, University of São Paulo, São Paulo, Brazil

* To whom correspondence should be addressed.
José Mauro Vieira Jr, E-mail: josemvjr{at}usp.br



  Abstract

Background. The pleiotropic actions of statins have been largely explored. These drugs have been tested in several models of progressive renal disease, most of them accompanied by hypertension. We sought to investigate more closely the effects of simvastatin on renal interstitial fibrosis due to unilateral ureteral obstruction (UUO).

Methods. Munich-Wistar rats were submitted to UUO and studied after 14 days. Animals were divided into two groups: vehicle (VH) or simvastatin (SIMV) 2 mg/kg b.i.d. by gavage. At sacrifice kidneys were harvested for morphology, mRNA and protein analysis. RT-PCR was done to assess expression of collagen I and III, fibronectin, MCP-1, TGF-{beta}1 and bFGF. Protein expression was assessed by western blot (TGF-{beta}) and immunostaining (macrophage, lymphocyte, PCNA, vimentin and {alpha}-smooth muscle actin). Contralateral kidneys (CL) were used as controls.

Results. SIMV-treated animals had less severe renal inflammation. MCP-1 was markedly expressed in obstructed kidneys and diminished with SIMV (48.9± 2.5 vs 64.3±3.1 OD in VH, P<0.01). Interstitial fibrosis (IF) was significantly attenuated with SIMV (8.2±1.3 vs 13.2±0.6%, P<0.01 SIMV vs VH), which was confirmed by a decrease in collagen I and fibronectin renal expression. Vimentin, a marker of dedifferentiation, was expressed in tubular cells of VH and decreased with SIMV treatment. {alpha}-SMA, a marker of myofibroblast-type cells, was increased in renal interstitium of VH rats and SIMV significantly reduced its expression. PCNA was increased in the UUO kidneys, but SIMV did not decrease tubular or interstitial proliferating cells. TGF-{beta}1, which was highly induced in the obstructed kidneys, decreased at the post-transcriptional level with SIMV treatment (5.35±0.75 vs 13.10±2.9 OD in VH, P<0.05). bFGF mRNA was also overexpressed in the obstructed kidneys, although SIMV treatment did not significantly decrease its expression.

Conclusions. SIMV had an evident protective effect on renal interstitial inflammation and fibrosis. It is conceivable that by attenuating inflammation, SIMV prevented tubular activation and transdifferentiation, two processes largely involved in the renal fibrosis of the UUO model.

Keywords: inflammation; interstitial fibrosis; MCP-1; simvastatin; transdifferentiation; unilateral ureteral obstruction.
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