11 Citations (Scopus)

Abstract

Statins are reported to alleviate renal fibrosis in animal models with ureteral obstruction. However, the molecular mechanism of this antifibrotic effect is still unclear. Pressure force is an important mechanism contributing to induction and progression of tubulointerstitial fibrogenesis in ureteric obstruction. In this study, we investigated the influence of rosuvastatin on pressure-induced fibrotic responses in rat renal tubular cells (NRK-52E). We established an in vitro pressure culture system to study pressure-induced fibrotic responses in NRK-52E cells. When NRK-52E cells were cultured in the pressure culture system, 60 mmHg of pressure induced the expression of connective tissue growth factor (CTGF), transforming growth factor (TGF)-β, fibronectin, Smad3, and phospho-Smad3. Rosuvastatin significantly reduced these pressure-induced fibrotic responses at concentrations above 10 μM. Rosuvastatin also reduced the TGF-β-induced expression of fibronectin and CTGF in NRK-52E cells. Pretreatment with rosuvastatin significantly induced prostacyclin (PGI2) generation, but reduced pressure-induced prostaglandin E2 (PGE2). PGI2 synthase small interfering RNA (siRNA) transfection significantly inhibited rosuvastatin-induced peroxisome proliferator-activated receptor α activation. The blockage of peroxisome proliferator-activated receptor α by siRNA transfection reduced the inhibitory effect of rosuvastatin on pressure-induced fibrotic responses. N-[2-(cyclohexyloxy)-4-nitrophenyl]- methanesulfonamide (NS398), a specific inhibitor of cyclooxygenase-2, diminished pressure-induced PGE2 generation, and also reduced pressure-induced fibrotic responses. Additionally, PGE2 decreased the antifibrotic effect of rosuvastatin. In conclusion, rosuvastatin reduces pressure-induced fibrotic responses in renal tubular cells by enhancing the PGI 2-peroxisome proliferator-activated receptor α pathway and reducing PGE2 generation.

Original languageEnglish
Pages (from-to)65-73
Number of pages9
JournalEuropean Journal of Pharmacology
Volume700
Issue number1-3
DOIs
Publication statusPublished - Jan 30 2013

Keywords

  • Fibrosis
  • Pressure
  • Prostacyclin
  • Prostaglandin E2
  • Renal tubular cells
  • Rosuvastatin

ASJC Scopus subject areas

  • Pharmacology

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