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.
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.
|Wei, Qingqing; Dong, Zheng (2014) HDAC4 blocks autophagy to trigger podocyte injury: non-epigenetic action in diabetic nephropathy. Kidney Int 86:666-8|
|Ma, Zhengwei; Wei, Qingqing; Dong, Guie et al. (2014) DNA damage response in renal ischemia-reperfusion and ATP-depletion injury of renal tubular cells. Biochim Biophys Acta 1842:1088-96|
|He, Liyu; Livingston, Man J; Dong, Zheng (2014) Autophagy in acute kidney injury and repair. Nephron Clin Pract 127:56-60|
|Livingston, Man J; Dong, Zheng (2014) Autophagy in acute kidney injury. Semin Nephrol 34:17-26|
|Yang, Yuan; Liu, Hong; Liu, Fuyou et al. (2014) Mitochondrial dysregulation and protection in cisplatin nephrotoxicity. Arch Toxicol 88:1249-56|
|Wei, Qingqing; Dong, Guie; Chen, Jian-Kang et al. (2013) Bax and Bak have critical roles in ischemic acute kidney injury in global and proximal tubule-specific knockout mouse models. Kidney Int 84:138-48|
|Zhang, Dongshan; Li, Yijian; Liu, Yu et al. (2013) Paclitaxel ameliorates lipopolysaccharide-induced kidney injury by binding myeloid differentiation protein-2 to block Toll-like receptor 4-mediated nuclear factor-?B activation and cytokine production. J Pharmacol Exp Ther 345:69-75|
|Zhan, Ming; Brooks, Craig; Liu, Fuyou et al. (2013) Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology. Kidney Int 83:568-81|
|Wang, Shixuan; Wei, Qingqing; Dong, Guie et al. (2013) ERK-mediated suppression of cilia in cisplatin-induced tubular cell apoptosis and acute kidney injury. Biochim Biophys Acta 1832:1582-90|
|Patil, Mallikarjun; Pabla, Navjotsingh; Dong, Zheng (2013) Checkpoint kinase 1 in DNA damage response and cell cycle regulation. Cell Mol Life Sci 70:4009-21|
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