title: Heat Shock Protein 72 Antagonizes STAT3 Signaling to Inhibit Fibroblast Accumulation in Renal Fibrogenesis.
abstract: 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.
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, China; Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China.
authors: Yi
authors: Y
authors: Zhou
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, China; Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China.
authors: Shirong
authors: S
authors: Cao
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, China; Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China.
authors: Huiyan
authors: H
authors: Li
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, China; Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China.
authors: Xuan
authors: X
authors: Peng
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, China; Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China.
authors: Yating
authors: Y
authors: Wang
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, China; Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China.
authors: Jinjin
authors: J
authors: Fan
authors: Laboratory for Kidney Pathology, Inc., Nashville, Tennessee.
authors: Yihan
authors: Y
authors: Wang
authors: Department of Medicine, Alpert Medical School and Rhode Island Hospital of Brown University, Providence, Rhode Island.
authors: Shougang
authors: S
authors: Zhuang
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, China; Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. Electronic address: yuxq@mail.sysu.edu.
authors: Xueqing
authors: X
authors: Yu
authors: Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, China; Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China. Electronic address: haipingmao@126.com.
authors: Haiping
authors: H
authors: Mao
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology
chemical_list: D050884:HSP72 Heat-Shock Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat