ARID3a, a repressor in aged kidney progenitors?

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Abstract ARID3a, a DNA-binding protein, is a member of a large family of proteins associated with epigenetic functions. ARID3a is expressed in hematopoietic progenitors where its expression and functions are altered with age. Our recent studies indicate that ARID3a expression can be induced in multiple cell types from healthy adults in association with inflammatory processes, and particularly with expression of Type I interferons. Induction of ARID3a in adult cell types leads to differential gene expression patterns that are cell type-specific. We linked ARID3a expression to kidney development in the mouse, where absence of ARID3a in bulk-cultured mouse kidneys resulted in generation of developmentally plastic cells. Surprisingly, these cells spontaneously developed into complex structures that express mature kidney markers when plated in semi-solid cultures. This finding led us to determine if ARID3a is expressed in human adult kidneys. Our preliminary data indicate that ARID3a expression in the human kidney appears to increase with age and that it is co-expressed in three subsets of cells with progenitor surface markers. The same subsets from younger individuals express little ARID3a. We hypothesize that increased ARID3a expression in aged individuals impairs the functions of those ARID3a-expressing kidney progenitors compared to cells from younger individuals that express lower levels of ARID3a. In Aim 1, we will test this hypothesis by inhibiting ARID3a expression in these three cell subsets from aged individuals and comparing the ability of those cells to proliferate and differentiate in vitro to cells from the same individuals with ARID3a. We will also compare these cells to progenitors from younger adults. Further, we hypothesize that ARID3a alters gene expression patterns in aged individuals resulting in changes in function. In Aim 2, we will identify genes and pathways affected by ARID3a expression in older adult progenitor cells to determine the pathway(s) associated with decreased responses in aged kidneys. Together, these experiments will provide new information about the potential effects of ARID3a in aged kidneys and could ultimately result in new therapeutics for kidney repair. In addition, results from these studies may identify markers relevant for aging and inflammatory responses in other tissues.