Apoptotic Gene Regulation in Renal Pathology

这种竞争性更新的目标是阐明肾小管细胞损伤的凋亡机制，这是一个主要的 急性肾衰竭的病因在上一个赠款期间，我们和其他人已经证明了参与 肾小管细胞凋亡在缺血性和肾毒性肾损伤中的作用重要的是，这些研究表明， 线粒体信号的关键作用。在病理状态下， 线粒体被透化，导致促凋亡因子如细胞色素C的释放。 线粒体膜透化涉及促凋亡Bcl-2家族蛋白Bax和巴克; 然而，其内在机制尚不清楚。我们的初步研究显示 肾小管细胞凋亡过程中线粒体的形态学变化。重要的是， 似乎是线粒体透化的决定因素。我们发现：1）诱导细胞凋亡后， 丝状线粒体变得片段化; 2）抑制线粒体分裂或片段化防止 线粒体膜透化和凋亡; 3）Drp-1和Endo-B1，两种分裂蛋白， 在肾小管细胞凋亡过程中转运到线粒体; 4）Endo-B1特异性地与Bax相互作用; 5）而 Bax和巴克都参与线粒体的透化，巴克似乎在线粒体的透化中具有独特的作用。 线粒体碎裂我们假设在凋亡诱导后，Endo-B1与Bax相互作用， 导致Bax易位至线粒体。与此同时，Drp-1被募集到线粒体中并与 用巴克诱导线粒体分裂和碎裂。线粒体膜变化 片段化促进Bax形成凋亡孔，导致促凋亡蛋白的释放。 因素我们将通过三个具体目标来检验这一假设。目的1将证明线粒体 体内碎片化及其在急性肾损伤中的作用。目的2将确定Endo-B1参与 肾小管细胞凋亡过程中Bax的激活与线粒体断裂。目标3将阐明 凋亡过程中巴克和Bax对线粒体形态动力学的调节。这些研究 有望推进肾小管细胞凋亡过程中线粒体损伤的基本理解。 这项研究的完成可能为缺血性和肾毒性肾损害提供新的治疗策略。 失败

The goal of this competitive renewal is to elucidate the apoptotic mechanism of tubular cell injury, a major cause of acute renal failure. During the last grant period, we and others have demonstrated the involvement of tubular cell apoptosis in ischemic and nephrotoxic renal injury. Importantly, these studies have suggested a pivotal role for mitochondrial signaling. Under the pathological condition, the outer membrane of mitochondria is permeabilized, resulting in the release of apoptogenic factors such as cytochrome c. Mitochondrial membrane permeabilization involves the pro-apoptotic Bcl-2 family proteins, Bax and Bak; however, the underlying mechanism is unclear. Our preliminary studies have now revealed a striking morphological change of mitochondria during tubular cell apoptosis. Importantly, the morphological change appears to be a determinant of mitochondrial permeabilization. We found: 1) upon apoptosis induction, filamentous mitochondria become fragmented; 2) inhibition of mitochondrial fission or fragmentation prevents mitochondrial membrane permeabilization and apoptosis; 3) Drp-1 and Endo-B1, two fission proteins, translocate to mitochondria during tubular cell apoptosis; 4) Endo-B1 specifically interacts with Bax; 5) while both Bax and Bak contribute to mitochondrial permeabilization, Bak appears to have a unique role in mitochondrial fragmentation. We hypothesize that upon apoptosis induction, Endo-B1 interacts with Bax, leading to Bax translocation to mitochondria. Meanwhile, Drp-1 is recruited to mitochondria and collaborates with Bak to induce mitochondrial fission and fragmentation. Membrane changes during mitochondrial fragmentation facilitate the formation of apoptotic pores by Bax, leading to the release of apoptogenic factors. We will test this hypothesis by three specific aims. Aim 1 will demonstrate mitochondrial fragmentation in vivo and its role in acute kidney injury. Aim 2 will determine the involvement of Endo-B1 in Bax activation and mitochondrial fragmentation during tubular cell apoptosis. Aim 3 will elucidate the regulation of mitochondrial morphological dynamics by Bak and Bax during apoptosis. The studies are expected to advance the fundamental understanding of mitochondrial injury during tubular cell apoptosis. Completion of the research may provide novel therapeutic strategies for ischemic and nephrotoxic renal failure.