Acute kidney injury (AKI) is the most common renal disease requiring hospitalization and is associated with significant mortality. There remains no reliable treatment modality for acute kidney injury. 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. Our prior work uncovered a unique, unanticipated role for sulfotransferase 1C2 (SULT1C2) in changing mitochondria physiology to confer protection against ischemic injury. Since we found SULT1C2 is highly up-regulated in proteomic screens of mitochondria isolated from ischemia-preconditioned kidneys, we tested whether kidneys transduced with plasmids bearing SULT1C2 are resistant to ischemia preconditioning. The goal of this proposal is to delineate the extent of the contribution that SULT1C2 makes to altered cell metabolism resulting in an ischemia preconditioned state. We will test the hypothesis that the mitochondria adaptation due to ischemia preconditioning is due in part to direct action of sulfotransferase 1C2 on mitochondria function brought about by changing cholesterol sulfate levels in mitochondria membranes. 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. Studies in specific objective 1 will test the hypothesis that sulfotransferase 1C2 changes mitochondria respirome composition and physiology due to changes in membrane lipid organization. These experiments will utilize a proteomic approach of label-free-quantitative mass spectroscopy to identify biochemical similarities in different models of resistance.
Specific aim 2 will test the hypothesis that sulfotransferase 1C2 requires mitochondria receptors to convert cholesterol to cholesterol sulfate. Lastly aim 3 will test the hypothesis that inhibition of sulfotransferase 1C2 or down-regulation of sulfotransferase 1C2 markedly attenuates cellular protection against ischemia reperfusion injury. These studies will investigate post- ischemic mitochondria respiratory capacity, mitochondrial polarization, renal hemodynamics and renal function protection. Overall, the proposed studies will help provide an understanding of cytoprotective strategies and identify potential therapeutic targets to manage the severity of AKI.
Acute kidney injury (AKI) occurs in 5-7% of hospitalized patients with evidence pointing to rising incidence due to an aging US population. AKI is estimated to cost 17 billion dollars in aggregate health care costs annually. At present there is no FDA approved treatment to either prevent or treat AKI. Sensitivity to ischemia is a primary cause of AKI and resistance to AKI occurs with ischemia preconditioning or naturally occurring genetic resistance. Sulfotransferase 1C2 was identified in screens of genetic and physiologic resistant states. Our preliminary work shows significant mitochondria physiologic changes brought about by sulfotransferase 1C2?s enzymatic conversion of cholesterol to cholesterol sulfate. This proposal tests the hypothesis that sulfotransferase 1C2 is a significant contributing factor in the cellular physiologic changes associated with ischemia preconditioning. Understanding ischemia preconditioning is important to develop novel therapies to prevent acute kidney injury.
