HSP72 attenuates renal tubular cell apoptosis and interstitial fibrosis in obstructive nephropathy.
Although heat shock protein 72 kDa (HSP72) protects tubular epithelium from a variety of acute insults, its role in chronic renal injury and fibrosis is poorly characterized. In this study, we tested the hypothesis that HSP72 reduces apoptosis and epithelial-to-mesenchymal transition (EMT), important contributors to tubular cell injury in vitro and in vivo. In rats, orally administered geranylgeranylacetone (GGA), an agent that selectively induces HSP72, markedly reduced both apoptosis and cell proliferation in tubular epithelium and decreased both interstitial fibroblast accumulation and collagen I deposition after unilateral ureteric obstruction, a model of chronic renal tubulointerstitial fibrosis and dysfunction. In cultured renal NRK52E cells, exposure to TGF-beta1 induced EMT and apoptosis, major causes of renal fibrosis and tubular atrophy, respectively. Exposure to a pan-caspase inhibitor (ZVAD-FMK) prevented TGF-beta1-induced apoptosis but did not reduce EMT. In contrast, selective HSP72 expression in vitro inhibited EMT caused by TGF-beta1 as indicated by preserving the E-cadherin expression level and alpha-smooth muscle actin induction. Small interfering RNA directed against HSP72 blocked the cytoprotective effects of HSP72 overexpression on EMT in TGF-beta1-exposed cells. Taken together, our data indicate that HSP72 ameliorates renal tubulointerstitial fibrosis in obstructive nephropathy by inhibiting both renal tubular epithelial cell apoptosis and EMT.
Mao
Haiping
H
Department of Nephrology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Li
Zhilian
Z
Zhou
Yi
Y
Li
Zhijian
Z
Zhuang
Shougang
S
An
Xin
X
Zhang
Baiyu
B
Chen
Wei
W
Nie
Jing
J
Wang
Zhiyong
Z
Borkan
Steven C
SC
Wang
Yihan
Y
Yu
Xueqing
X
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology; D005355:Fibrosis; D050884:HSP72 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D007676:Kidney Failure, Chronic / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors
D000590:Amino Acid Chloromethyl Ketones; D004224:Diterpenes; D050884:HSP72 Heat-Shock Proteins; D053773:Transforming Growth Factor beta1; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C031049:geranylgeranylacetone