Kidney Week

Abstract: FR-OR17

ATP-Citrate Lyase (ACLY) Is a Key Modulator of Nephron Progenitor Cell Fate Decisions In Vivo

Session Information

• Development, Organoids, and Genetic Models of Kidney Diseases
  November 03, 2023 | Location: Room 105, Pennsylvania Convention Center
  Abstract Time: 05:24 PM - 05:33 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 600 Development, Stem Cells, and Regenerative Medicine

Authors

• Tortelote, Giovane G., Tulane University School of Medicine, New Orleans, Louisiana, United States

Giovane G. Tortelote, MS, PhD

• Diniz, Fabiola, Tulane University School of Medicine, New Orleans, Louisiana, United States

Fabiola Diniz,

• Hilliard, Sylvia, Tulane University School of Medicine, New Orleans, Louisiana, United States

Sylvia Hilliard,

• El-Dahr, Samir S., Tulane University School of Medicine, New Orleans, Louisiana, United States

Samir S. El-Dahr,

Group or Team Name

• Tortelote Lab.

Background

Nephron endowment at birth impacts long-term renal and cardiovascular health and is contingent on the nephron progenitor cells (NPC) pool. NPC fate decisions are influenced by the cell’s metabolome. Acetyl-CoA is a key molecule involved in cellular metabolism. Acetyl-CoA provides energy and serves as a metabolic intermediate necessary for cellular growth and differentiation. However, the in vivo requirement of Acetyl-CoA for kidney development is still unknown.

Methods

Six2^GFPCRE;Acly^f/+ males were bred to floxed Acly homozygous female mice to generate embryos lacking Acly expression in the NPC and nephrogenic lineage. Immunofluorescence (E14.5, E16.5, and P0) and organ culture (E12.5+24h) were used to characterize the mutant phenotype. NPC and fluorescence intensity quantifications were performed with ImageJ. H&E staining was used for morphological analysis and glomeruli counts.

Results

Removal of Acly (a gene that regulates cytosolic availability of acetyl-CoA) from the NPC pool during embryonic development led to a reduction in glomeruli counts (≈ 30%), depletion of cap-mesenchyme (WT = 44 vs MUT = 32 NPC/niche), and increased Wnt4 expression at birth. Cap depletion and UB abnormalities were evident at E14.5 and E16.5. Sodium-acetate supplementation to cultured E13.5 mutant kidneys rescued cap mesenchyme depletion without hindering differentiation. Furthermore, Six2Cre-mediated removal of Acly led to the upregulation of Acyl-CoA Synthetase Short Chain Family Member 2 (Acss2) in nascent proximal tubules (PT) exclusively. Upregulation of Acss2 suggested a compensatory route for acetyl-CoA production during PT nephrogenesis. The upregulation of Acss2 was accompanied by an increased abundance of Hnf4a, a key regulator of proximal tubule maturation.

Conclusion

In conclusion, our findings revealed a crucial role of acetyl-CoA metabolism during kidney development and provided insights into the molecular mechanisms underlying early nephrogenesis. In addition, we identified a new molecular target with therapeutic potential to offset the programming process during early life to prevent the development of adult kidney disease.

Funding

• NIDDK Support