Elucidating the Role of NAD+ and PARylation in Nephron Endowment

Background: There is broad variation in nephron endowment in humans; infants born with fewer nephrons have increased risk of chronic kidney disease (CKD) in adulthood. Nicotinamide adenine dinucleotide (NAD+) is a critical co-factor in most energy producing reactions. It is synthesized from nutritional precursors. Published work proposes that NAD+ availability affects kidney health from development through to disease in a potentially poly(ADP-ribose) polymerase 1 (PARP1)-dependent fashion. Fetuses are frequently exposed to maternal conditions that lower NAD+ abundance including malnutrition and diabetes. These conditions are also associated with reduced fetal nephron endowment (oligonephronia) and adulthood CKD. Little is known about the direct impact of maternal NAD+ on fetal nephrogenesis. My preliminary data in mice show that maternal NAD+ deficiency can cause oligonephronia that can be rescued by maternal supplementation of NAD+ precursors. Published data show that NAD+ dependent PARP1 plays a role in progenitor cell differentiation in multiple cells and tissues during development. Hypothesis: I hypothesize that reduced maternal NAD+ precursor availability may impair fetal nephrogenesis by reducing nephron progenitor cell (NPC) PARP1 activity. Aims: In this proposal, Aim 1 will study how exogenous NAD+ affects NPC differentiation. Aim 2 will assess how cellular compartmentalization of NAD+ influences nephron progenitor cell differentiation using innovative biosensors to characterize how NAD+ biosynthesis compartmental fluxes change through renal development. Aim 3 will elucidate if and how PARP1 mediates the effect of NAD+ on nephrogenesis. The findings from these Aims may provide novel insight into the nutritional aspects of the maternal-fetal interactions that influence renal development and may suggest therapeutic targets for developmental nephron augmentation. Impact: This five-year proposal will provide the training and mentorship necessary for me to develop into an independent investigator studying the metabolism-driven phenomena of renal development, with a specific focus on NAD+. To accomplish this, I have developed a detailed career development plan integrating the outstanding mentorship and scientific environment at UT Southwestern with focused training in developmental biology to successfully transition to independence as an expert at the intersection of metabolism, nutrition, maternal-fetal health, and kidney development.