title: Heat shock factor 1 induces crystallin-αB to protect against cisplatin nephrotoxicity.
abstract: Cisplatin, a wildly used chemotherapy drug, induces nephrotoxicity that is characterized by renal tubular cell apoptosis. In response to toxicity, tubular cells can activate cytoprotective mechanisms, such as the heat shock response. However, the role and regulation of the heat shock response in cisplatin-induced nephrotoxicity remain largely unclear. In the present study, we demonstrated the induction of heat shock factor (Hsf)1 and the small heat shock protein crystallin-αB (CryAB) during cisplatin nephrotoxicity in mice. Consistently, cisplatin induced Hsf1 and CryAB in a cultured renal proximal tubular cells (RPTCs). RPTCs underwent apoptosis during cisplatin treatment, which was increased when Hsf1 was knocked down. Transfection or restoration of Hsf1 into Hsf1 knockdown cells suppressed cisplatin-induced apoptosis, further supporting a cytoprotective role of Hsf1 and its associated heat shock response. Moreover, Hsf1 knockdown increased Bax translocation to mitochondria and cytochrome c release into the cytosol. In RPTCs, Hsf1 knockdown led to a specific downregulation of CryAB. Transfection of CryAB into Hsf1 knockdown cells diminished their sensitivity to cisplatin-induced apoptosis, suggesting that CryAB may be a key mediator of the cytoprotective effect of Hsf1. Taken together, these results demonstrate a heat shock response in cisplatin nephrotoxicity that is mediated by Hsf1 and CryAB to protect tubular cells against apoptosis.
authors.affiliation: Antibody Drug Engineering Laboratory of Henan Province, Henan University School of Medicine, Kaifeng, Henan, China; and Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lou
authors.affiliation: Antibody Drug Engineering Laboratory of Henan Province, Henan University School of Medicine, Kaifeng, Henan, China; and Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.
authors.forename: Yanzhong
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Antibody Drug Engineering Laboratory of Henan Province, Henan University School of Medicine, Kaifeng, Henan, China; and.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Antibody Drug Engineering Laboratory of Henan Province, Henan University School of Medicine, Kaifeng, Henan, China; and Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia zdong@Augusta.edu.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002945:Cisplatin; D003459:Crystallins / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use*; D055785:Gene Knockdown Techniques; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D003459:Crystallins; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D014157:Transcription Factors; D020169:Caspases; D002945:Cisplatin
keywords: cisplatin nephrotoxicity; crystallin-αB; heat shock factor 1; heat shock response; renal tubular cell