Pax8-Hnf4a co-regulation in ischemic kidney injury

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The goals of this project are to 1) test the hypothesis that Pax8 expression controls sensitivity to ischemic kidney injury in the mature proximal tubule by promoting transcription of Hnf4a targets and 2) facilitate a path to an independent research program for the PI. Ischemic acute kidney injury (AKI) is a common clinical syndrome associated with significant mortality, yet no treatments are in routine clinical use. Ischemic AKI most strongly affects the proximal tubule, in part due to the unique metabolic pathways used by this nephron segment. Understanding the molecular and genetic mechanisms that establish this unique metabolic profile could lead to a better understanding of ischemic AKI pathogenesis and new therapeutic targets. As part of the associated K08 award, we discovered that proximal-tubule-selective depletion of the transcription factor Pax8 resulted in a population of proximal tubule cells resistant to kidney injury. Analysis of the transcriptome of these cells revealed alterations in genes associated with proximal tubule metabolism. However, the genes affected by Pax8 depletion were not preferentially associated with sites of Pax8 chromatin binding. Analysis of other transcription factors associated with genes affected by Pax8 depletion revealed a central role of Hnf4a. These observations suggest the hypothesis that Pax8 expression controls sensitivity to ischemic kidney injury in the proximal tubule by promoting transcription of Hnf4a targets. This project will investigate this hypothesis by determining the role of Pax8 in the chromatin localization of Hnf4a and by identifying metabolic pathways coregulated by Pax8 and HNF4a in response to ischemic injury in vivo. The targets identified in each of these aims will form the basis for independent research support studying the molecular and genetic determinants of ischemic AKI risk.