title: Protein Kinase CδSuppresses Autophagy to Induce Kidney Cell Apoptosis in Cisplatin Nephrotoxicity.
abstract: Nephrotoxicity is a major adverse effect in cisplatin chemotherapy, and renoprotective approaches are unavailable. Recent work unveiled a critical role of protein kinase Cδ(PKCδ) in cisplatin nephrotoxicity and further demonstrated that inhibition of PKCδnot only protects kidneys but enhances the chemotherapeutic effect of cisplatin in tumors; however, the underlying mechanisms remain elusive. Here, we show that cisplatin induced rapid activation of autophagy in cultured kidney tubular cells and in the kidneys of injected mice. Cisplatin also induced the phosphorylation of mammalian target of rapamycin (mTOR), p70S6 kinase downstream of mTOR, and serine/threonine-protein kinase ULK1, a component of the autophagy initiating complex.In vitro, pharmacologic inhibition of mTOR, directly or through inhibition of AKT, enhanced autophagy after cisplatin treatment. Notably, in both cells and kidneys, blockade of PKCδsuppressed the cisplatin-induced phosphorylation of AKT, mTOR, p70S6 kinase, and ULK1 resulting in upregulation of autophagy. Furthermore, constitutively active and inactive forms of PKCδrespectively enhanced and suppressed cisplatin-induced apoptosis in cultured cells. In mechanistic studies, we showed coimmunoprecipitation of PKCδand AKT from lysates of cisplatin-treated cells and direct phosphorylation of AKT at serine-473 by PKCδin vitroFinally, administration of the PKCδinhibitor rottlerin with cisplatin protected against cisplatin nephrotoxicity in wild-type mice, but not in renal autophagy-deficient mice. Together, these results reveal a pathway consisting of PKCδ, AKT, mTOR, and ULK1 that inhibits autophagy in cisplatin nephrotoxicity. PKCδmediates cisplatin nephrotoxicity at least in part by suppressing autophagy, and accordingly, PKCδinhibition protects kidneys by upregulating autophagy.
authors: Departments of *Emergency Medicine and zdong@gru.edu 715653110@qq.com.|Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; and.
authors: Dongshan
authors: D
authors: Zhang
authors: Departments of *Emergency Medicine and.
authors: Jian
authors: J
authors: Pan
authors: Departments of *Emergency Medicine and.
authors: Xudong
authors: X
authors: Xiang
authors: Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; and.|Nephrology, Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
authors: Yu
authors: Y
authors: Liu
authors: Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; and.
authors: Guie
authors: G
authors: Dong
authors: Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; and.
authors: Man J
authors: MJ
authors: Livingston
authors: Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; and.
authors: Jian-Kang
authors: JK
authors: Chen
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Xiao-Ming
authors: XM
authors: Yin
authors: Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; and zdong@gru.edu 715653110@qq.com.|Nephrology, Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
authors: Zheng
authors: Z
authors: Dong
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000502:physiology*; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity; D007668:Kidney / Q000166:cytology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D051379:Mice; D051745:Protein Kinase C-delta / Q000502:physiology*
chemical_list: D051745:Protein Kinase C-delta; D002945:Cisplatin
keywords: apoptosis; cisplatin; nephrotoxicity