Acute kidney injury (AKI) occurs in 5-7% of all hospital admissions and recent evidence has shown that even minor changes in renal function are associated with increased risk of death. In the ICU, AKI is associated with 50% mortality, a statistic which has not changed even with dialysis therapy. In fact the Acute Renal Failure Trial Network study, a combined VA and NIH sponsored dialysis dosing study, showed no change in mortality statistics when comparing dialysis dosing. Clearly new approaches are urgently needed to address this life-threatening disease. Given the fact that the VA population is aging, prone to diabetes and hypertension, AKI is a major health problem in this group. Upon completion of this VA Merit Review, investigators in the renal community will have new targets for small molecular drug discovery that should ameliorate the mortality associated with AKI.
Acute kidney injury (AKI) is the most common renal disease requiring hospitalization and is associated with 50% mortality in the ICU. There remains no reliable treatment modality for acute kidney injury that has impacted the dismal survival statistics. Clearly new approaches are urgently required. In the setting of ischemia or hypoxic injury, early alterations in mitochondrial structure impair cellular energetics, activate cell death pathways, increase oxygen free radical generation and may influence renal hemodynamics. Different models of naturally or experimentally induced resistance to ischemic injury may help to identify biochemical, cellular and physiological events underlying the injury process and provide potential targets for therapeutic intervention. The confluence of data suggests that an enhanced regulation of stress related proteins or mitochondria regulated energetics may impart protection in animal models of resistance to AKI The overarching hypothesis of this application is that mitochondrial adaptation to hypoxia entrains mitochondria toward a biosynthetic activity and decreased ATP generative activity. This adaptation has common features in cells primed by ischemia preconditioning or background genetic traits that confer resistance to ischemia. In these studies, we will utilize two different models of resistance to AKI; 1) a genetic model of the Brown Norway rat and Brown Norway derived consomic strains of rats, and 2) a model of experimentally induced ischemic preconditioning to determine proteins that confer ischemic protection. Studies in specific objective 1 will test the hypothesis that genetic and experimentally induced models of resistance to I/R (ischemia/reperfusion) have common biochemical properties at the level of the mitochondria. These experiments will utilize a proteomic approach of label- free-quantitative mass spectroscopy to identify biochemical similarities in different models of resistance. Studies in specific objective 2 will investigate the potential protective effect of proteins identified in resistant states. Mitochondrial targeted genes derived from specific aim 1 will be tested an in vitro model of proximal tubule cells and the preservation of mitochondrial function and cellular integrity in response to hypoxia evaluated. Studies in specific objective 3 will evaluate the effec of mitochondrial targeting on the short and long-term response to kidney injury in vivo. Specific objective 4 will study how mitochondria adapt in response to transgene expression, ischemia preconditioning or genetic modifications. These studies will investigate post-ischemic mitochondria respiratory capacity, mitochondrial polarization and the resulting influence on ROS generation and renal hemodynamics. Overall, the proposed studies will help provide an understanding of cytoprotective strategies and identify potential therapeutic targets to manage the severity of AKI.
