The embryonic renal interstitium plays critical regulatory roles in renal development. However, our knowledge of its cellular composition, the functions of its individual cellular constituents, and the full scope of its involvement in renal formation and function is far from complete. We found that in the deeper cortex (excluding the part of the cortex from the surface of the kidney to where S-shaped bodies locate) and medulla, the response of Wnt/p-catenin signaling in the embryonic renal interstitium is confined to about two layers of cells adjacent to ureteric trunks (Wnt/p-catenin target cells), and the expression of certain genes in these cells were disrupted when (3-catenin was ablated specifically from the renal interstitium. The overall objective of this proposal is to test the hypothesis the HDACl/2 inhibit epigenetically Wnt/(3-catenin signaling which regulates the fate of it target renal interstitial cells and their function in regulating kidney development. Specifically, using a combination of mouse genetics, biochemical and molecular biology, we will determine the identity ofthe interstitial cells that do and do not respond to Wnt/p-catenin signaling during normal development and their fates in response to ablation of Wnt/p-catenin signaling (Aimi). Further, we will test the hypothesis that the Wnt/p-catenin signaling target interstitial cells affect the proper formation of loop-of- Henle and microvascular endothelium in the developing kidney (Aim2). HDAC1 and HDAC2, histone deacetylases that remove acetyl groups from either core histones or non-histone proteins, function in either an epigenetic or a non-epigenetic manner.
In specific Aim 3, we will test the hypothesis that HDACl/2 inhibits Wnt/p-catenin signaling in the renal interstitium epigenetically. The proposed work will significantly expand our mechanistic understanding ofthe regulation of renal interstitial cell fates, and uncover additional functions of the renal interstitium during kidney development. Further, it will define the cellular composition of the majority ofthe renal interstitium which will facilitate future work of targeted manipulation ofthe renal interstitium to reveal additional functions ofthe renal interstitium. The knowledge and information acquired from the proposed research will also assist diagnosis and treatment of congenital renal diseases in children.

Public Health Relevance

Congenital anomaly in the kidney and urinary tract accounts for about 35% of end-stage renal diseases in children (USRDS, 2011). Our proposed research will extend and enhance the mechanistic understanding of the regulation of renal interstitial cell fates and of their regulatory roles in kidney development. It will facilitate development of strategies for diagnosis and treatment of pediatric renal diseases resulted from renal malformation.

National Institute of Health (NIH)
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University of Virginia
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El-Dahr, Samir; Hilliard, Sylvia; Aboudehen, Karam et al. (2014) The MDM2-p53 pathway: multiple roles in kidney development. Pediatr Nephrol 29:621-7
Galarreta, Carolina I; Grantham, Jared J; Forbes, Michael S et al. (2014) Tubular obstruction leads to progressive proximal tubular injury and atubular glomeruli in polycystic kidney disease. Am J Pathol 184:1957-66
McLaughlin, Nathan; Wang, Fenglin; Saifudeen, Zubaida et al. (2014) In situ histone landscape of nephrogenesis. Epigenetics 9:222-35
Chevalier, Robert L; Forbes, Michael S; Galarreta, Carolina I et al. (2014) Responses of proximal tubular cells to injury in congenital renal disease: fight or flight. Pediatr Nephrol 29:537-41