Regulation of Apoptosis in Renal Ischemia

描述（由申请人提供）：抑制细胞凋亡可预防缺血性肾损伤（IRI）。最近的报道表明，抑制转录因子p53可防止IRI后的细胞凋亡并改善肾功能；然而，p53诱导细胞凋亡的信号通路尚不清楚。我们发现两个促凋亡p53转录靶点Siva和PERP （p53凋亡效应与PMP-22相关）在IRI中被特异性激活。抑制Siva可防止小鼠细胞凋亡，并对IRI具有功能保护作用。Siva的过度表达通过caspase依赖和独立的机制导致肾近端小管细胞（PTC）的凋亡细胞死亡。我们的长期研究目标是阐明调控PTC凋亡细胞死亡的细胞信号通路，从而确定干预这些通路治疗急性肾损伤（AKI）的策略。本研究的目的是描述Siva和PERP整合其信号诱导肾PTC细胞凋亡的机制，并干预其信号通路以治疗IRI。核心假设是Siva和PERP的激活通过tnf受体CD27刺激外源性凋亡通路，诱导线粒体通透性释放凋亡因子，并转运到细胞核募集凋亡诱导因子（apoptosis inducing factor， AIF），触发iri后PTC凋亡。该假设的有效性将通过三个具体目标来验证，即确定Siva- cd27和Siva- PERP相互作用引发caspase依赖性和独立型细胞凋亡的机制，并确定其信号在肾缺血小鼠模型中诱导细胞凋亡和损害肾功能的体内功能意义。这些研究的意义包括确定了一种可能启动PTC凋亡的新途径，这可能为AKI的预后和管理提供新的干预机会，具有重要的临床意义。

DESCRIPTION (provided by applicant): Inhibition of apoptosis protects against ischemic renal injury (IRI). Recent reports demonstrate that inhibition of the transcription factor p53 prevents apoptosis and improves renal function following IRI; however, the signaling pathways by which p53 induces apoptosis are yet to be elucidated. We identified two pro-apoptotic p53 transcriptional targets Siva and PERP (p53 apoptosis effector related to PMP-22) to be specifically activated in IRI. Inhibition of Siva prevented apoptosis and offered functional protection from IRI in mice. Over expression of Siva led to apoptotic cell death of renal proximal tubular cells (PTC) in vitro by caspase-dependent and independent mechanisms. Our long term research goal is to elucidate the cellular signaling pathways that regulate PTC apoptotic cell death, in order to identify strategies to intervene in those pathways to treat acute kidney injury (AKI). The objective of the proposed work is to delineate the mechanisms by which Siva and PERP integrate their signals to induce apoptosis in renal PTC and intervene in their signaling pathways to treat IRI. The central hypothesis is that activation of Siva and PERP stimulate the extrinsic apoptotic pathway via the TNF-receptor, CD27, induce mitochondrial permeability to release apoptogenic factors and translocate to the nucleus to recruit apoptosis inducing factor (AIF) to trigger PTC apoptosis post-IRI. The validity of the hypothesis will be tested by pursuing three specific aims that are aimed at determining the mechanisms by which Siva-CD27 and Siva- PERP interactions elicit caspase-dependent and independent apoptosis and determine the in vivo functional significance of their signaling in inducing apoptosis and impairing renal function in mouse model of renal ischemia. The significance of the studies includes the identification of a novel pathway that may initiate PTC apoptosis that may provide new opportunities for intervention with important clinical implications, both for prognosis and management of AKI. PUBLIC HEALTH RELEVANCE: Acute kidney injury is a devastating clinical syndrome with a 50% mortality rate affecting 5-7% of all hospitalized patients. Currently, there are no accepted therapies available to treat this condition. Interfering with p53-mediated apoptotic programs may allow the development of novel therapeutic strategies to reduce the mortality and morbidity. The latter outcome could have a dramatic impact on the quality of life and reducing the health care cost associated with acute kidney injury.