TY - JOUR
T1 - Rosuvastatin inhibits pressure-induced fibrotic responses via the expression regulation of prostacyclin and prostaglandin E2 in rat renal tubular cells
AU - Chen, Cheng Hsien
AU - Cheng, Chung Yi
AU - Chen, Yen Cheng
AU - Sue, Yuh Mou
AU - Hsu, Yung Ho
AU - Tsai, Wei Lun
AU - Chen, Tso Hsiao
PY - 2013/1/30
Y1 - 2013/1/30
N2 - 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.
AB - 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.
KW - Fibrosis
KW - Pressure
KW - Prostacyclin
KW - Prostaglandin E2
KW - Renal tubular cells
KW - Rosuvastatin
UR - http://www.scopus.com/inward/record.url?scp=84874076294&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84874076294&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2012.12.017
DO - 10.1016/j.ejphar.2012.12.017
M3 - Article
C2 - 23276663
AN - SCOPUS:84874076294
VL - 700
SP - 65
EP - 73
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-3
ER -