Renal Cell Injury by Ischemia: a role for Bid

描述（由申请人提供）：肾脏缺血性损伤导致急性肾衰竭，尽管进行了深入研究，但仍与高死亡率相关。虽然缺血性肾衰竭的发展涉及多种因素，并可能在几个阶段进行，但它最终是由肾小管细胞的亚致死性和致死性损伤引起的。然而，缺血导致肾小管细胞损伤的分子基础仍不清楚。我们研究的长期目标是确定负责肾小管细胞损伤的关键因素，并设计有效的策略来减少缺血性肾脏病理。我们发现，培养的肾小管细胞的缺血性损伤涉及Bax的激活，Bax是一种促进死亡的Bcl-2家族蛋白。我们最近发现，Bid，另一种促死亡分子，在肾缺血期间被激活。有趣的是，Bid可以作用于Bax的上游，导致线粒体损伤和细胞死亡。重要的是，我们的初步研究表明，缺血性肾小管细胞损伤和肾功能衰竭减少投标敲除小鼠。基于这些观察结果，我们假设Bid在肾缺血期间激活后，与Bax相互作用并协同破坏线粒体，导致细胞损伤、组织损伤和肾衰竭的发展。我们将通过以下三个具体目标来验证这一假设：（1）使用Bid敲除模型证明Bid参与缺血性肾损伤的确凿证据;（2）使用Bax敲除模型确定Bax在缺血性肾损伤和肾衰竭中的作用;（3）确定Bid和Bax在肾小管细胞中的物理和功能相互作用。这些研究有望证明Bid和Bax对缺血性肾细胞损伤的调节作用。它们还将为Bcl-2家族蛋白，特别是Bid和Bax介导的细胞损伤机制提供新的见解。最后，完成这项研究将有助于设计遗传和药理学策略，以改善缺血性肾功能衰竭的目标出价，Bax和他们的相互作用。

DESCRIPTION (provided by applicant): 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 ischemic tubular 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 involvement of 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.