PILOT--CITED PROTEINS IN RENAL DEVELOPMENT AND DISEASE

Vanderbilt University, Nashville TN

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Abstract

Abnormal regulation of epithelial differentiation in the metanephric kidney gives rise to congenital defects in renal development that may result in progressive. renal insufficiency. Furthermore, many types of renal. injury are associated with de-differentiation and proliferation of epithelia in the adult kidney, suggesting that these processes may, at least in part, result from a breakdown and/or reactivation of developmental programs that regulate epithelial cell differentiation. In a screen to identify factors involved in the regulation of this process, we have shown that the three mammalian CITED family members, CITED1, 2 and 4, are expressed in the metanephric mesenchyme and epithelial cell derivatives of the developing rat kidney. CITED proteins are non-DNA binding transcriptional co-factors that interact with components of the general transcriptional machinery and selectively modify different transcriptional responses. CITED1 has a restricted distribution in undifferentiated metanephric mesenchyme, CITED2 is expressed in the mesenchyme and epithelia, while CITED4 is only expressed in epithelia. Over-expression of CITED1 blocks the ability of explanted metanephric mesenchymes to undergo epithelial morphogenesis, suggesting that it may function in the coordinate regulation of mesenchyme to epithelial transformation in the developing kidney. We hypothesize that the three mammalian Cited family members have distinct and potentially combinatorial roles in the regulation of nephrogenesis, and that de-differentiation of epithelial cells in different models of renal injury is associated with reactivation of this developmental program of genes. Three Specific Aims are proposed to test these hypotheses: Specific Aims 1 and 2 will establish the expression patterns of Cited family genes in mouse kidney development and in the adult following renal injury; Specific Aim 3 will evaluate the morphological features of embryonic and adult kidneys from the Cited1, 2 and 4 knockout and heterozygous mutant mice that will be provided by our collaborators, Dr. Shioda and Dr. Bhattacharya. These pilot studies will provide the background for future experiments using Cited mutant mice to investigate the functional role of these proteins in renal development and in the regulation of epithelial de-differentiation associated with renal injury.