Cisplatin is one of the most widely used and most potent cancer therapy drugs. However, the use of cisplatin is associated with a major side-effect of nephrotoxicity, resulting in acute kidney injury (cisplatin-AKI) in over 25% of patients. The mechanism of cisplatin-AKI remains unclear and effective renoprotective approaches are not available. We have recently unveiled a critical role of PKC? in cisplatin-AKI and, remarkably, inhibition of PKC? not only protects kidneys but can also enhance the chemotherapy effect of cisplatin in tumors. Despite these findings, it is largely unclear how PKC? inhibition can protect kidneys, while killing cancer cells. We have demonstrated autophagy induction in cisplatin-AKI and its critical role of kidney protection. Moreover, mitophagy that removes damaged mitochondria via autophagy has been suggested. Mechanistically, our preliminary work supports the involvement of p53 and PKC? in autophagy regulation during cisplatin-AKI. We hypothesize that: 1) mitophagy is activated during cisplatin-AKI and accounts largely for the renoprotective effect of autophagy; 2) p53 contributes to autophagy induction in cisplatin-AKI, whereas PKC? plays an autophagy suppressive role; and 3) inhibition of PKC? may protect kidneys during cisplatin chemotherapy by enhancing autophagy. To test this hypothesis, we propose to: 1) elucidate mitophagy as a protective mechanism of autophagy in cisplatin-AKI; 2) determine the autophagy-promoting role of p53 in cisplatin-AKI; 3) delineate the autophagy-suppressing role of PKC? in cisplatin-AKI; and 4) test the hypothesis that PKC? inhibition protects kidneys through enhancing autophagy by analyzing the effects of PKC? inhibition in autophagy-suppressed and non-suppressed mice. Completion of the research will not only gain significant insights into autophagy protection and regulation in renal pathogenesis, but will also elucidate autophagy as a mechanism of the renoprotective effect of PKC? inhibition, suggesting a novel therapeutic strategy for kidney protection during chemotherapy in cancer patients.

Public Health Relevance

Cisplatin, a widely used chemotherapy drug, has major side-effects in kidneys resulting in acute kidney injury in over 25% of patients. We have unveiled a critical role of PKC? in cisplatin-induced kidney injury and, remarkably, inhibition of PKC? not only protects kidneys but can also enhance the chemotherapy effect of cisplatin in tumors. This application may identify autophagy as the renoprotective mechanism of PKC? inhibition and gain insights into autophagy regulation in kidneys.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK087843-06A1
Application #
9034718
Study Section
Special Emphasis Panel (ZRG1-DKUS-A (03))
Program Officer
Kimmel, Paul
Project Start
2010-04-01
Project End
2020-02-29
Budget Start
2016-03-15
Budget End
2017-02-28
Support Year
6
Fiscal Year
2016
Total Cost
$387,111
Indirect Cost
$132,433
Name
Georgia Regents University
Department
Biology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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