Section of Pediatric Nephrology, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
Nat Commun. 2023 Nov 25;14(1):7733. doi: 10.1038/s41467-023-43513-7.
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.
出生时的肾单位数量会影响肾脏和心血管系统的长期健康，而这取决于肾祖细胞（NPC）池。糖酵解的调节对于确定 NPC 命运至关重要，但潜在的机制尚不清楚。我们通过 RNA 测序和定量蛋白质组学相结合的方法，在 NPC 中鉴定出 267 个共同受到 Wnt 激活或糖酵解抑制作用的基因。受影响的途径中有几个集中在乙酰辅酶 A 上，它是葡萄糖代谢的副产物。值得注意的是，糖酵解抑制会下调甲羟戊酸/胆固醇途径的关键基因，并刺激 NPC 分化。补充醋酸钠可以挽救糖酵解抑制的作用，并有利于 NPC 的维持，而不会阻碍肾发生。通过 Six2Cre 介导去除三羧酸循环酶 ATP-柠檬酸裂解酶（Acly），该酶将柠檬酸转化为乙酰辅酶 A，会导致 NPC 池耗竭、肾小球数量减少，并增加出生时的 Wnt4 表达。醋酸钠补充剂可以抵消 Acly 缺失对帽-间充质的影响。我们的研究结果表明，乙酰辅酶 A 代谢在肾脏发育中起着关键作用，并为操纵肾发生和预防成人肾脏疾病开辟了新的途径。
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