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

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  • Fabiola Diniz

    (Tulane University School of Medicine)

  • Nguyen Yen Nhi Ngo

    (Tulane University School of Medicine)

  • Mariel Colon-Leyva

    (Tulane University School of Medicine)

  • Francesca Edgington-Giordano

    (Tulane University School of Medicine)

  • Sylvia Hilliard

    (Tulane University School of Medicine)

  • Kevin Zwezdaryk

    (Tulane University School of Medicine)

  • Jiao Liu

    (Tulane University School of Medicine)

  • Samir S. El-Dahr

    (Tulane University School of Medicine)

  • Giovane G. Tortelote

    (Tulane University School of Medicine)

Abstract

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.

Suggested Citation

  • Fabiola Diniz & Nguyen Yen Nhi Ngo & Mariel Colon-Leyva & Francesca Edgington-Giordano & Sylvia Hilliard & Kevin Zwezdaryk & Jiao Liu & Samir S. El-Dahr & Giovane G. Tortelote, 2023. "Acetyl-CoA is a key molecule for nephron progenitor cell pool maintenance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43513-7
    DOI: 10.1038/s41467-023-43513-7
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