Protein kinase Cd suppresses autophagy to induce kidney cell apoptosis in cisplatin nephrotoxicity

Dongshan Zhang, Jian Pan, Xudong Xiang, Yu Liu, Guie Dong, Man Jiang Livingston, Jiankang Chen, Xiao Ming Yin, Zheng Dong

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 PKCδ not 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 PKCδ suppressed the cisplatin-induced phosphorylation of AKT, mTOR, p70S6 kinase, and ULK1 resulting in upregulation of autophagy. Furthermore, constitutively active and inactive forms of PKCδ respectively enhanced and suppressed cisplatin-induced apoptosis in cultured cells. In mechanistic studies, we showed coimmunoprecipitation of PKCδ and AKT from lysates of cisplatin-treated cells and direct phosphorylation of AKT at serine-473 by PKCδ in vitro. Finally, administration of the PKCδ inhibitor rottlerin with cisplatin protected against cisplatin nephrotoxicity in wild-typemice, 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. PKCδ mediates cisplatin nephrotoxicity at least in part by suppressing autophagy, and accordingly, PKCδ inhibition protects kidneys by upregulating autophagy.

Original languageEnglish (US)
Pages (from-to)1131-1144
Number of pages14
JournalJournal of the American Society of Nephrology
Volume28
Issue number4
DOIs
StatePublished - Apr 1 2017

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Autophagy
Protein Kinases
Cisplatin
Protein Kinase C
Apoptosis
Kidney
Sirolimus
Phosphorylation
Phosphotransferases
Protein C Inhibitor
Protein Kinase Inhibitors
Serine
Cultured Cells
Up-Regulation

ASJC Scopus subject areas

  • Nephrology

Cite this

Protein kinase Cd suppresses autophagy to induce kidney cell apoptosis in cisplatin nephrotoxicity. / Zhang, Dongshan; Pan, Jian; Xiang, Xudong; Liu, Yu; Dong, Guie; Livingston, Man Jiang; Chen, Jiankang; Yin, Xiao Ming; Dong, Zheng.

In: Journal of the American Society of Nephrology, Vol. 28, No. 4, 01.04.2017, p. 1131-1144.

Research output: Contribution to journalArticle

Zhang, Dongshan ; Pan, Jian ; Xiang, Xudong ; Liu, Yu ; Dong, Guie ; Livingston, Man Jiang ; Chen, Jiankang ; Yin, Xiao Ming ; Dong, Zheng. / Protein kinase Cd suppresses autophagy to induce kidney cell apoptosis in cisplatin nephrotoxicity. In: Journal of the American Society of Nephrology. 2017 ; Vol. 28, No. 4. pp. 1131-1144.
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