Simvastatin attenuates renal inflammation, tubular transdifferentiation and interstitial fibrosis in rats with unilateral ureteral obstruction.
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-beta1 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-beta1, 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.
Vieira
José Mauro
JM
Internal Medicine, Renal Division, University of São Paulo, São Paulo, Brazil. josemvjr@usp.br
Mantovani
Eduardo
E
Rodrigues
Leonardo Tavares
LT
Dellê
Humberto
H
Noronha
Irene Lourdes
IL
Fujihara
Clarice Kazue
CK
Zatz
Roberto
R
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000378:metabolism
D000199:Actins; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D005353:Fibronectins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D003094:Collagen; D019821:Simvastatin