Renal cell death and ischemic acute kidney injury (AKI) result from BCL2 protein-mediated mitochondrial membrane injury. How Bax, the quintessential "bad actor" of the BCL2 family causes outer mitochondrial membrane injury and renal cell death is uncertain. We hypothesize that interaction between conformationally active Bax and nucleophosmin (NPM), a recently described Bax chaperone, is required to form cytosolic complexes that translocate Bax to mitochondria, cause renal cell deat and impair kidney function. We propose that ischemic (AKI) can be inhibited at several steps by: reducing Bax activation, limiting NPM-Bax complex formation, or preventing mitochondrial fragmentation that increases mitochondrial susceptibility to "Bax Attack". Since Hsp70 (Hsp72kDa) likely interrupts the ischemic cell death pathway at each step, and a Bax blocking peptide prevents NPM-Bax complex formation, we anticipate that both maneuvers will be highly effective in preventing and accelerating recovery from ischemic AKI. In four AIMS, we will determine: (1) To what extent is conformational Bax activation during renal ischemia regulated by Akt or GSK3?, stress kinases known to mediate renal cell survival. The protective role of Hsp70 on both Akt and GSK3? will be explored~ (2) To what extent is the nucleophosmin-Bax complex required for renal cell injury? We propose that renal ischemia causes regulated NPM translocation from the nucleus into the cytosol, where it complexes with active Bax, enhances mitochondrial Bax accumulation and cell death~ (3) How does Hsp70 decrease stress-induced mitochondrial fragmentation and increase resistance to Bax Attack? We will characterize the mechanism(s) by which Hsp70 prevents mitochondrial fragmentation and Bax Attack and identify additional therapeutic targets in ischemic AKI and (4): To what extent can ischemic AKI be prevented and renal recovery be accelerated? We propose that Hsp70 and a Bax blocking peptide, agents that limit NPM and Bax toxicity, will effectively prevent and treat renal ischemia in vivo. These studies identify new targets of renal ell death that are amenable to intervention and determine the efficacy of Hsp70 induction and disruption of NPM-Bax complex as therapeutic strategies for preventing or accelerating recovery from ischemic AKI, a major challenge to public health for which there is no current therapy.
Ischemic Acute Kidney Injury (AKI) with organ failure is a common, often a life- threatening consequence of reduced blood flow to this critical organ. No effective prevention or treatment is currently available for this disease. In this application, we explore new observations about the mechanisms of renal cell death that will inform novel approaches to therapy for ischemia that are readily applicable to human AKI. The proposed studies will identify key signals in renal cell death pathway and determine the extent to which non-toxic maneuvers can be used to treat the consequences of kidney ischemia, a major cause of morbidity and mortality, before or after the insult has occurred.
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