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.
(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.
|Mei, Shuqin; Livingston, Man; Hao, Jielu et al. (2016) Autophagy is activated to protect against endotoxic acute kidney injury. Sci Rep 6:22171|
|Zhang, Dongshan; Pan, Jian; Xiang, Xudong et al. (2016) Protein Kinase CÎ´ Suppresses Autophagy to Induce Kidney Cell Apoptosis in Cisplatin Nephrotoxicity. J Am Soc Nephrol :|
|Havasi, Andrea; Dong, Zheng (2016) Autophagy and Tubular Cell Death in the Kidney. Semin Nephrol 36:174-88|
|Wei, Qingqing; Liu, Yong; Liu, Pengyuan et al. (2016) MicroRNA-489 Induction by Hypoxia-Inducible Factor-1 Protects against Ischemic Kidney Injury. J Am Soc Nephrol 27:2784-96|
|Tang, Chengyuan; Dong, Zheng (2016) Mitochondria in Kidney Injury: When the Power Plant Fails. J Am Soc Nephrol 27:1869-72|
|Liu, Zhiwen; Wang, Shixuan; Mi, Qing-Sheng et al. (2016) MicroRNAs in Pathogenesis of Acute Kidney Injury. Nephron 134:149-153|
|Tang, Chengyuan; Cai, Juan; Dong, Zheng (2016) Mitochondrial dysfunction in obesity-related kidney disease: a novel therapeutic target. Kidney Int 90:930-933|
|Lou, Qiang; Hu, Yanzhong; Ma, Yuanfang et al. (2016) Heat shock factor 1 induces crystallin-Î±B to protect against cisplatin nephrotoxicity. Am J Physiol Renal Physiol 311:F94-F102|
|Wang, Shixuan; Dong, Zheng (2016) Environmental hit on a genetic basis in polycystic kidney disease. Am J Physiol Renal Physiol 311:F1358-F1359|
|Zhang, Wei; Zhou, Xiangjun; Zhang, Hao et al. (2016) Extracellular vesicles in diagnosis and therapy of kidney diseases. Am J Physiol Renal Physiol 311:F844-F851|
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