Concomitant use of rapamycin and rosiglitazone delays the progression of polycystic kidney disease in Han:SPRD rats: a study of the mechanism of action.

Abstract

Attributing to their antiproliferative effect, both rapamycin and peroxisome proliferator-activated receptor-γ (PPARγ) can halt the progression of autosomal dominant polycystic kidney disease (ADPKD). Whether combined use could enhance this effect is unknown. The present study used rapamycin and the PPARγ agonist rosiglitazone concomitantly to observe their combined effects on the proliferation of ADPKD cyst-lining epithelial cells and the progression of ADPKD in Han:SPRD rats. Concomitant use of the two drugs inhibited the proliferation of WT9-12 cells significantly through a superimposition effect. Rosiglitazone inhibited the phosphorylation of mammalian target of rapamycin p70S6K. Concomitant use of rosiglitazone and rapamycin further downregulated the p-p70S6K level. Rosiglitazone also inhibited the phosphorylation of Akt and antagonized the activation of Akt induced by rapamycin. Concomitant use of rosiglitazone and rapamycin significantly retarded the deterioration of renal function, decreased cyst cell proliferation and interstitial fibrosis in Han:SPRD rats. Rapamycin significantly increased cholesterol levels in the blood, whereas rosiglitazone mitigated rapamycin-induced hyperlipidemia. These results indicate that the effects of concomitant use of rosiglitazone and rapamycin in inhibiting the proliferation of WT9-12 cells and delaying the progression of ADPKD in Han:SPRD rats are stronger than those of either drug alone. The present study may provide a new strategy for the long-term treatment of ADPKD.