Deletion of NuRD component Mta2 in nephron progenitor cells causes developmentally programmed FSGS

Basta, J.; Robbins, L.; Stout, L.; Brennan, M.; Shapiro, J.; Chen, M.; Denner, D.; Baldan, A.; Messias, N.; Madhavan, S. M.; Parikh, S. V.; Rauchman, M.

doi:10.1101/2023.10.18.562984

bioRxiv · 10.1101/2023.10.18.562984

Deletion of NuRD component Mta2 in nephron progenitor cells causes developmentally programmed FSGS

Basta, J.·Robbins, L.·Stout, L.·Brennan, M.·Shapiro, J.·Chen, M.·Denner, D.·Baldan, A.·Messias, N.·Madhavan, S. M.·Parikh, S. V.·Rauchman, M.

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Abstract

Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi- organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of Mta2 in nephron progenitor cells. Mta2 is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.

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Basta, J., Robbins, L., Stout, L., Brennan, M., Shapiro, J., Chen, M., Denner, D., Baldan, A., Messias, N., Madhavan, S. M., Parikh, S. V., Rauchman, M.. 2023-10-20. Deletion of NuRD component Mta2 in nephron progenitor cells causes developmentally programmed FSGS. https://doi.org/10.1101/2023.10.18.562984

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