Metabolic programming of nephron progenitor cell fate.

Metabolic pathways are one of the first responses at the cellular level to maternal/fetal interface stressors. Studies have revealed the previously unrecognized contributions of intermediary metabolism to developmental programs. Here, we provide an overview of cellular metabolic pathways and the cues that modulate metabolic states. We discuss the developmental and physiological implications of metabolic reprogramming and the key role of metabolites in epigenetic and epiproteomic modifications during embryonic development and with respect to kidney development and nephrogenesis.

Acetyl-CoA is a key molecule for nephron progenitor cell pool maintenance.

Nephron endowment at birth impacts long-term renal and cardiovascular health, and it is contingent on the nephron progenitor cell (NPC) pool. Glycolysis modulation is essential for determining NPC fate, but the underlying mechanism is unclear. Combining RNA sequencing and quantitative proteomics we identify 267 genes commonly targeted by Wnt activation or glycolysis inhibition in NPCs. Several of the impacted pathways converge at Acetyl-CoA, a co-product of glucose metabolism. Notably, glycolysis inhibition downregulates key genes of the Mevalonate/cholesterol pathway and stimulates NPC differentiation. Sodium acetate supplementation rescues glycolysis inhibition effects and favors NPC maintenance without hindering nephrogenesis. Six2Cre-mediated removal of ATP-citrate lyase (Acly), an enzyme that converts citrate to acetyl-CoA, leads to NPC pool depletion, glomeruli count reduction, and increases Wnt4 expression at birth. Sodium acetate supplementation counters the effects of Acly deletion on cap-mesenchyme. Our findings show a pivotal role of acetyl-CoA metabolism in kidney development and uncover new avenues for manipulating nephrogenesis and preventing adult kidney disease.