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Protein Kinase C? Suppresses Autophagy to Induce Kidney Cell Apoptosis in
Cisplatin Nephrotoxicity
#MMPMID27799485
Zhang D
; Pan J
; Xiang X
; Liu Y
; Dong G
; Livingston MJ
; Chen JK
; Yin XM
; Dong Z
J Am Soc Nephrol
2017[Apr]; 28
(4
): 1131-1144
PMID27799485
show ga
Nephrotoxicity is a major adverse effect in cisplatin chemotherapy, and
renoprotective approaches are unavailable. Recent work unveiled a critical role
of protein kinase C? (PKC?) in cisplatin nephrotoxicity and further demonstrated
that inhibition of PKC? 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 PKC?
suppressed the cisplatin-induced phosphorylation of AKT, mTOR, p70S6 kinase, and
ULK1 resulting in upregulation of autophagy. Furthermore, constitutively active
and inactive forms of PKC? respectively enhanced and suppressed cisplatin-induced
apoptosis in cultured cells. In mechanistic studies, we showed
coimmunoprecipitation of PKC? and AKT from lysates of cisplatin-treated cells and
direct phosphorylation of AKT at serine-473 by PKC?in vitro Finally,
administration of the PKC? inhibitor 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 PKC?, AKT, mTOR, and
ULK1 that inhibits autophagy in cisplatin nephrotoxicity. PKC? mediates cisplatin
nephrotoxicity at least in part by suppressing autophagy, and accordingly, PKC?
inhibition protects kidneys by upregulating autophagy.
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