Heat Shock Protein 72 Antagonizes STAT3 Signaling to Inhibit Fibroblast Accumulation in Renal Fibrogenesis.

Heat shock protein 72 (HSP72) has been shown to attenuate unilateral ureteral obstruction-induced kidney fibrosis. It remains unknown whether HSP72 has direct effects on fibroblast proliferation in the renal fibrotic evolution. Herein, we first confirmed that increased HSP72 expression occurred in fibrotic human kidneys. Using three different animal models of kidney fibrosis, pharmacological down-regulation or genetic deletion of endogenous HSP72 expression exacerbated STAT3 phosphorylation, fibroblast proliferation, and tubulointerstitial fibrosis. In contrast, treatment with geranylgeranyl acetone, a specific inducer of HSP72, reduced phosphorylated STAT3 and protected animals from kidney fibrosis. In cultured renal interstitial fibroblasts, overexpression of HSP72 blocked transforming growth factor (TGF)-β1-induced cell activation and proliferation, as evidenced by inhibiting expression of α-smooth muscle actin, fibronectin, and collagen I/III, as well as by reducing cell numbers and DNA synthesis. Mechanical studies showed that overexpressed HSP72 attenuated TGF-β-induced phosphorylation and nuclear translocation of STAT3 and its downstream protein expression. However, siRNA knockdown of HSP72 increased TGF-β-induced STAT3 activity and fibroblast proliferation. Ectopic expression of a constitutively active STAT3 conferred resistance to HSP72 inhibition of fibroblast proliferation. Thus, HSP72 blocks fibroblast activation and proliferation in renal fibrosis via targeting the STAT3 pathway and may serve as a novel therapeutic agent for chronic kidney disease regardless of the etiology. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Citation

Yi Zhou, Shirong Cao, Huiyan Li, Xuan Peng, Yating Wang, Jinjin Fan, Yihan Wang, Shougang Zhuang, Xueqing Yu, Haiping Mao. Heat Shock Protein 72 Antagonizes STAT3 Signaling to Inhibit Fibroblast Accumulation in Renal Fibrogenesis. The American journal of pathology. 2016 Apr;186(4):816-28

Mesh Tags

Substances

PMID: 26851345

search → result