The central theme of this Center of Excellence in Pediatric Nephrology is “Kidney Development: Cell fate and Precursors of Disease in the Young and Adult”. It is incrasingly evident that abnormalities in renal development are responsible for most cases of renal disease. 40% of end-stage kidney disease cases in children are caused by congenital anomalies of the kidney and urinary tract. Low nephron endowment and the attendant reduction in functional renal mass leads to hypertension and progressive renal disease. Unfortunately, the basic mechanisms that determine nephron endowment are not completely understood.
The kidney is a highly vascularized organ that in the normal adult receives about 20% of the cardiac output. The unique spatial arrangement of the kidney arterioles with each nephron is crucial for the regulation of renal blood flow, glomerular filtration rate and other specialized kidney functions that maintain homeostasis. Thus, the proper and timely assembly of the arterioles with their respective nephrons is a crucial morphogenetic event leading to the formation of a functioning kidney necessary for independent extrauterine life. Many kidney diseases have primary or secondary vascular lesions and renal failure is frequently associated with defective angiogenesis. Progressive renal disease is characterized by deterioration of the renal microvasculature which correlates with the development of glomerular and tubulointerstitial fibrosis.
In light of the importance of the acquisition of proper nephron endowment and microvascular structure to the normal function of the kidney the overall hypothesis of this Center is that regulation of progenitor endowment, cell fate, and maintenance of the differentiated cell phenotypes are crucial in the acquisition and preservation of the architectural and functional integrity of the kidney. This hypothesis implies that early developmental events and cellular choices (such as epigenetic decisions in response to environmental cues) affect the physiological responses and the progression of kidney disease and/or repair mechanisms in the maturing and adult individual. The research projects of Center investigators address the most fundamental questions regarding the fate of two major progenitor compartments (cap mesenchyme and stroma) which give rise to most of the structures of the kidney during development (Figure 1): the epithelial nephron, its vasculature and the interstitium. In addition, their work examines the phenotypic and structural changes that occur as a result of two major causes of renal disease in children: obstructive nephropathy and congenital decrease in nephron endowment.
Three major projects and two initial pilot projects (Figure 1) test the following overall interrelated hypotheses:
- RBP-J is necessary for the differentiation of Foxd1+ and Renin+ progenitor cells and the establishment of cell identity epigenetic marks and gene-expression patterns that are responsible for the differentiation of the mural cells of the renal arterioles (Project 1, Gomez).
- Specific histone methylation and acetylation machineries are essential for epithelial nephron progenitor cell renewal, lineage determination, identity, and fate (Project 2, El Dahr).
- Formation of atubular glomeruli (ATG) a frequent, although under recognized, pathway for nephron loss due to obstructive renal injury is modulated by nephron endowment and events that control cell fate and repair upon release of obstruction (Project 3, Chevalier).
- p53 restricts Wnt/- β-catenin signaling in the nephron progenitor cells during mesenchymal-epithelial transformation (Pilot 1, Saifudeen).
- Jagged 1 regulates morphogenesis of the renal arterioles (Pilot 2, Belyea).