This competitive renewal application investigates how critical genes and pathways that determine renal epithelial cell differentiation, growth, and survival contribute to normal renal physiology and recovery from acute kidney injury. During previous funding periods, we have made significant breakthroughs in defining the mechanisms of Pax2 protein function in development and disease. Interactions between Pax proteins and epigenetic writers can imprint epithelial specific fates during development. In adults, the related gene Pax8 is expressed in all epithelial cells, whereas Pax2 is restricted to collecting ducts in the inner and outer medulla. How these two proteins function redundantly to control urine concentration and water resorption in the medulla will be defined using genetic, whole genomic, and cell biological methods. Preliminary data strongly indicate an essential role of Pax2/8 for the expression of urea, water, and ion channels. Furthermore, the function of Pax2 and Pax8 in recovery form acute renal injury will be examined in targeted mutants and animal model of ischemia reperfusion and nephrotoxicity. We propose that Pax genes are central to driving recovery in proximal tubules by promoting dedifferentiation of surviving cells, re-entry into mitosis, and resetting of epigenetic marks essential for maintaining a renal cell phenotype. Whole genome and transcriptome analyses, coupled to single cell methods, will delineate specific genes and pathways activated and repressed by Pax proteins during recovery such that novel potential targets for therapy may be illuminated.
This renewal will expand our investigations of the developmental regulators Pax2 and the related gene Pax8 into adult kidneys, using novel genetic mutations and biochemical methods to define their functions in the inner and outer medulla where regulation of urine concentration occurs. An essential role for Pax genes and proteins in activating and maintaining the expression of urea, water, and ion channels in the collecting ducts of adult kidneys will be examined. Furthermore, cell type specific mutations and single cell analyses will examine how Pax genes contribute to the regeneration of proximal tubule epithelia after acute kidney injury and to promote recovery.
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