Heat shock protein 90 inhibitor attenuates renal fibrosis through degradation of transforming growth factor-beta type II receptor

Abstract

The accumulation of extracellular matrix proteins in the interstitial area is the final common feature of chronic kidney diseases. Accumulating evidence suggests that transforming growth factor (TGF)-beta 1 promotes the development of renal fibrosis. Heat shock protein (Hsp) 90 inhibitors have been shown to repress TGF-beta 1 signaling, but whether they inhibit renal fibrosis is unknown. The purpose of this study is to determine the therapeutic efficacy of Hsp90 inhibitor on renal fibrosis. In TGF-beta 1-treated HK2 cells and unilateral ureteral obstruction (UUO) kidneys, we found that 17-allylamino-17-demethoxygeldanamycin (17AAG), an Hsp90 inhibitor, decreased the expression of alpha-smooth muscle actin, fibronectin, and collagen I and largely restored the expression of E-cadherin. 17AAG inhibited TGF-beta 1-mediated phosphorylation of Smad2, Akt, glycogen synthase kinase-3 beta, and extracellular signal-regulated kinase in HK2 cells. Inhibition of Hsp90 also blocked TGF-beta 1-mediated induction of snail1. This 17AAG-induced reduction was completely restored by simultaneous treatment with proteasome inhibitor MG132. Furthermore, 17AAG blocked the interaction between Hsp90 and TGF-beta type II receptor (T beta RII) and promoted ubiquitination of T beta RII, leading to the decreased availability of T beta RII. Smurf2-specific siRNA reversed the ability of 17AAG to inhibit TGF-beta 1 signaling. The effect of 17AAG on T beta RII expression and renal fibrosis was confirmed in UUO kidneys. These findings suggest that Hsp90 inhibitor prevents the development of renal fibrosis via a mechanism dependent on Smurf2-mediated degradation of T beta R11. Laboratory Investigation (2012) 92, 1583-1596; doi:10.1038/labinvest.2012.127; published online 10 September 2012