p53-Regulated Metabolic Fitness of Self-Renewing Nephron Progenitor Cells
Nearly 3-10% of all pregnancies are affected by abnormal glucose regulation. Infants of diabetic mothers (IDM) are at a four-fold higher risk for congenital malformations of kidneys, brain and heart, as well as antenatal, perinatal or neonatal morbidity. Renal defects include hypoplasia with a significant nephron deficit, agenesis, cystic kidneys, ureteral duplication and hydronephrosis. Congenital low nephron number is a common cause of pediatric renal failure, adult-onset hypertension and chronic kidney disease - all clinically significant diseases without a cure. Availability of nephron progenitor cells (NPC) and their efficient differentiation into nephrons are major determinants of nephron endowment. The Cited1+/Six2+ sub-compartment of the cap mesenchyme is the stem cell niche, and marks the definitive self-renewing NPC. A self-renewal defect would result in a loss of these cells and consequently a diminished progenitor pool. A fundamental question is what regulates the stemness of NPCs. In a conditional knock-out model of the transcription factor p53 from the nephron progenitor cells, we observed progressive and selective depletion of self-renewing progenitors, nephron deficit and adult-onset hypertension. RNA-Seq data indicate that top down-regulated genes regulate energy metabolism pathways. Preliminary mechanistic studies demonstrate decreased ATP and ROS levels in Six2p53-/- cells. Balanced ATP and biomass synthesis (nucleotides, amino acids etc.) via oxidative phosphorylation (Oxphos) and glycolysis, respectively, are critical drivers of self-renewal and proliferation. Cell competition studies in Drosophila implicate p53 as a sensor and key modulator of adaptive metabolic changes to maintain cell viability. Based on these data we hypothesize that p53 enables self-renewal of the NPC by maintaining metabolic homeostasis in response to niche cues. Our long-term goal is to define the role of p53 in integrating niche signals (nutrient, growth factors, variations in oxygen tension) with key sensory pathways (AMPK, mTOR, Hif1a). For this pilot study we propose to establish the metabolic profile of Cited1+/Six2+ cells, which is currently unknown, under normal, high and low glucose conditions, and evaluate Cited1+/Six2+ NPC cell fate after a metabolic switch (by pharmacological inhibition of glycolysis or Oxphos.

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