Cisplatin is one of the most widely used and most potent chemotherapy drugs. However, the use of cisplatin is associated with major side effects in normal tissues and organs, especially the kidneys, leading to acute kidney injury (AKI) and renal failure. The goal of our research is to delineate the cell signaling mechanism of cisplatin-AKI and identify effective strategies for renoprotection. Cisplatin-AKI, involving multiple factors, is nevertheless precipitated by renal tubular cell injury and death, and tissue damage. Recent research has revealed several upstream signaling pathways in tubular damage during cisplatin-AKI, including Src, MAPK, p53 and a rapid DNA damage response. However, it remains unclear how these pathways are regulated and integrated to result in an impressive renal pathology. Our preliminary studies demonstrated the first evidence for a role of PKC4 in cisplatin-AKI. Notably, while inhibition of PKC4 protected against cisplatin-induced kidney injury, it enhanced cisplatin-induced injury and death in multiple cancer cells lines and also in vivo in ovarian tumor xenografts. We hypothesize that: 1) PKC4 is a key regulator of cell signaling during cisplatin-induced kidney injury;2) PKC4 activation during cisplatin treatment involves a Src family kinase and after being activated, PKC4 may regulate p53 and/or MAPK signaling pathways to result in renal tubular apoptosis;and 3) inhibition of PKC4 not only protects kidneys but can also enhance the chemotherapy effects of cisplatin in tumors. We will test this hypothesis by three Specific Aims: 1) elucidate PKC4 activation in vivo during cisplatin-AKI and establish its pathogenic role by using gene knockout models;2) delineate the PKC4 signaling pathway that contributes to cisplatin-AKI;and 3) determine if blocking PKC4 can protect kidneys and enhance the anti-cancer effect of cisplatin in tumor-bearing animals. Completion of the project will not only gain novel mechanistic insights of AKI but may also discover a new and effective strategy for renoprotection during cisplatin-based chemotherapy.

Public Health Relevance

(Relevance) Over a quarter of patients receiving cisplatin-based chemotherapy develop renal problems, leading to acute kidney injury and renal failure. No effective approaches are currently available to protect the kidneys in these cancer patients. By revealing a new signaling mechanism of cisplatin injury, this project will significantly advance the understanding of acute kidney injury associated with cisplatin chemotherapy. Moreover, it may discover a clinically applicable strategy for renoprotection that not only protects kidneys but may also enhance the chemotherapy effects of cisplatin in tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK087843-05
Application #
8728198
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Kimmel, Paul
Project Start
2010-09-30
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
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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Wang, Shixuan; Liu, Aimin; Wu, Guangyu et al. (2018) The CPLANE protein Intu protects kidneys from ischemia-reperfusion injury by targeting STAT1 for degradation. Nat Commun 9:1234
Liu, Jing; Livingston, Man J; Dong, Guie et al. (2018) Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells. Cell Death Dis 9:322
Yan, Mingjuan; Shu, Shaoqun; Guo, Chunyuan et al. (2018) Endoplasmic reticulum stress in ischemic and nephrotoxic acute kidney injury. Ann Med 50:381-390
Li, Fanghua; Liu, Zhiwen; Tang, Chengyuan et al. (2018) FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury. FASEB J 32:3423-3433
Yang, Danyi; Livingston, Man J; Liu, Zhiwen et al. (2018) Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential. Cell Mol Life Sci 75:669-688
Li, Fanghua; Livingston, Man J; Dong, Zheng (2017) Protection of kidneys by magnesium in cisplatin chemotherapy: a fight between two metals. Am J Physiol Renal Physiol 313:F955-F956
Liu, Jing; Wei, Qingqing; Guo, Chunyuan et al. (2017) Hypoxia, HIF, and Associated Signaling Networks in Chronic Kidney Disease. Int J Mol Sci 18:
Zhang, Dongshan; Pan, Jian; Xiang, Xudong et al. (2017) Protein Kinase C? Suppresses Autophagy to Induce Kidney Cell Apoptosis in Cisplatin Nephrotoxicity. J Am Soc Nephrol 28:1131-1144
Zhou, Xiangjun; Zhang, Wei; Yao, Qisheng et al. (2017) Exosome production and its regulation of EGFR during wound healing in renal tubular cells. Am J Physiol Renal Physiol 312:F963-F970

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