The number of nephrons in human kidneys ranges from 300,000 to 2 million. Low nephron number is associated with hypertension and end-stage renal disease. In humans, nephrogenesis ends at 36 weeks of gestation due to depletion of nephron progenitors. No new nephrons will be formed after birth. Therefore, a better understanding of the regulators of nephrogenesis could lead to better interventions for improving nephron endowment. Currently, the molecular mechanisms that determine nephron endowment are poorly understood. Previous studies have shown that retinoic acid regulates the branching of the collecting duct in the developing mouse kidney. Since the nephrogenesis is coupled with the branching, the branching defect can lead to low nephron numbers. Consistent with this, maternal vitamin A deficiency in rats causes reduced nephron numbers. Interestingly, my preliminary data suggest that retinoic acid affects the nephron endowment by regulating nephron progenitors and their descendants. My goal is to better understand the molecular mechanisms of retinoic acid signaling in nephron formation. I hypothesize that retinoic acid signaling regulates mesenchymal to epithelial transition of nephron progenitor cells and maturation of the proximal tubule.
In Aim 1, I will test the hypothesis that retinoic acid regulates mesenchymal to epithelial transition using in vivo and in vitro experiments examining early nephrogenesis along with genomic analysis of retinoic acid receptor bound regions in nephron progenitor cells.
In Aim 2, I will determine if retinoic acid signaling controls maturation of the proximal tubule via in vivo and in vitro functional assays and identification of direct targets of retinoic acid signaling in proximal tubule cells. The results from this proposal will provide new insights into the molecular mechanisms of nephron endowment and nephron tubule maturation.
Maternal vitamin A deficiency causes a spectrum of kidney malformations. Although retinoic acid, the active metabolite of vitamin A, has been shown to regulate the branching of the collecting duct in the developing kidney, little is known about its effect on nephron progenitors and their descendants. In this proposal, we will study the molecular mechanisms of retinoic acid-mediated regulation of nephron endowment and nephron tubule maturation.
