Heat Shock Protein 90 Inhibitor Attenuates Renal Fibrosis Through Degradation of Transforming Growth factor-β Type II Receptor

Lab Invest. 2012 Nov;92(11):1583-96. doi: 10.1038/labinvest.2012.127. Epub 2012 Sep 10.

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)-β1 promotes the development of renal fibrosis. Heat shock protein (Hsp) 90 inhibitors have been shown to repress TGF-β1 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-β1-treated HK2 cells and unilateral ureteral obstruction (UUO) kidneys, we found that 17-allylamino-17-demethoxygeldanamycin (17AAG), an Hsp90 inhibitor, decreased the expression of α-smooth muscle actin, fibronectin, and collagen I and largely restored the expression of E-cadherin. 17AAG inhibited TGF-β1-mediated phosphorylation of Smad2, Akt, glycogen synthase kinase-3β, and extracellular signal-regulated kinase in HK2 cells. Inhibition of Hsp90 also blocked TGF-β1-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-β type II receptor (TβRII) and promoted ubiquitination of TβRII, leading to the decreased availability of TβRII. Smurf2-specific siRNA reversed the ability of 17AAG to inhibit TGF-β1 signaling. The effect of 17AAG on TβRII 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 TβRII.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoquinones / pharmacology*
  • Benzoquinones / therapeutic use
  • Cell Line
  • Disease Models, Animal
  • Fibrosis
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology
  • Kidney Diseases / prevention & control*
  • Lactams, Macrocyclic / pharmacology*
  • Lactams, Macrocyclic / therapeutic use
  • Male
  • Mice
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Smad Proteins / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • tanespimycin
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II