Ischemic injury of the kidneys leads to acute renal failure, which, despite intensive research, continues to be associated with high mortality. While the development of ischemic renal failure involves multiple factors and may proceed in several phases, it is ultimately precipitated by sublethal and lethal damage to the tubular cells. However, the molecular basis of tubular cell injury by ischemia remains unclear. The long-term goal of our research is to identify the key factors that are responsible for tubular cell injury and design effective strategies to diminish ischemic renal pathology. We showed that ischemic injury of cultured tubular cells involved the activation of Bax, a death-promoting Bcl-2 family protein. We found recently that Bid, another pro-death molecule, was activated during renal ischemia. Of interest, Bid could act upstream of Bax, leading to mitochondrial damage and cell death. Importantly, our preliminary studies demonstrated that ischemictubular cell injury and renal failure were diminished in Bid knockout mice. Based on these observations, we hypothesize that Bid, upon activation during renal ischemia, interacts and collaborates with Bax to disrupt mitochondria, contributing to the development of cell injury, tissue damage and renal failure. We will test this hypothesis by pursuing three specific aims: (1) to demonstrate conclusive evidence for the involvementof Bid in ischemic renal injury using Bid knockout models;(2) to determine the role of Bax in ischemic renal injury and renal failure using Bax knockout models;(3) to determine the physical and functional interactions between Bid and Bax in renal tubular cells. These studies are expected to demonstrate the regulation of ischemic renal cell injury by Bid and Bax. They will also provide new insights into cell injury mechanisms mediated by Bcl-2 family proteins, Bid and Bax in particular. Finally, completion of the research will facilitate the design of genetic and pharmacological strategies to ameliorate ischemic renal failure by targeting Bid, Bax and their interaction.
| Periyasamy-Thandavan, Sudharsan; Jiang, Man; Schoenlein, Patricia et al. (2009) Autophagy: molecular machinery, regulation, and implications for renal pathophysiology. Am J Physiol Renal Physiol 297:F244-56 |
| Jiang, Man; Wei, Qingqing; Pabla, Navjotsin et al. (2007) Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity. Biochem Pharmacol 73:1499-510 |
