title: Heat shock protein 90 inhibitor attenuates renal fibrosis through degradation of transforming growth factor-β 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)-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.
authors.affiliation: Department of Internal Medicine, Soon Chun Hyang University, Seoul, Korea. nohneph@schmc.ac.kr
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Noh
authors.forename: Hyun J
authors.initials: HJ
authors.lastname: Kim
authors.forename: Mi R
authors.initials: MR
authors.lastname: Yu
authors.forename: Wan-Young
authors.initials: WY
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: Jung H
authors.initials: JH
authors.lastname: Ryu
authors.forename: Soon H
authors.initials: SH
authors.lastname: Kwon
authors.forename: Jin S
authors.initials: JS
authors.lastname: Jeon
authors.forename: Dong C
authors.initials: DC
authors.lastname: Han
authors.forename: Fuad
authors.initials: F
authors.lastname: Ziyadeh
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004195:Disease Models, Animal; D005355:Fibrosis; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; C112765:tanespimycin; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II