ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: SA-PO309

Deletion of NuRD Component MTA2 in Nephron Progenitors Results in Renal Hypoplasia and Focal Segmental Glomerulosclerosis

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Basta, Jeannine M., Washington University in St. Louis, St. Louis, Missouri, United States
  • Robbins, Lynn, Washington University in St. Louis, St. Louis, Missouri, United States
  • Stout, Lisa, Washington University in St. Louis, St. Louis, Missouri, United States
  • Denner, Darcy Renee, Washington University in St. Louis, St. Louis, Missouri, United States
  • Rauchman, Michael I., Washington University in St. Louis, St. Louis, Missouri, United States
Background

The Nucleosome Remodeling and Deacetylase Complex (NuRD) is a large multi-protein, evolutionarily conserved chromatin remodeling complex that harnesses the power of ATP via the ATPase Chd4 (Mi2β) to mediate nucleosome sliding and remodeling. It also has histone deacetylase activity via Hdac 1/2. We showed that the NuRD component Mi2β and the association between Sall1-NuRD is required for the regulation of nephron progenitor cells (NPCs).

Methods

In this study we deleted the NuRD specific component Mta2 in Six2+ NPCs.

Results

Mutant mice were viable, although mild renal hypoplasia was evident at embryonic day (E)14-16 (kidney area/body weight 41.2±2.6 vs 53.6±1.7 mm2/gm). Immunostaining for nephron segment specific markers showed that the nephrogenic zone was not reduced and all differentiating nephron structures appeared normal in the mutant. RNA-seq analysis at E17 showed a number of downregulated genes important for metabolic pathways (23 genes, p=9.78X10-4), indicating reduced metabolic fitness of NPCs may account for renal hypoplasia. By 2 months of age Mta2 mutant mice developed proteinuria (1614±469 vs 53±15 ug albumin/mg creatinine, n= 20 mut, 13 control). Analysis of mutant kidneys revealed findings consistent with focal segmental glomerulosclerosis (FSGS), including mesangial hypercellularity, segmental glomerular scarring, and tip lesions. At 6 months of age albuminuria progressed in the mutant (7110±3739 vs 25±4, n=8 mut 8 control); histopathology showed an increase in globally sclerotic glomeruli, proliferation of parietal epithelial cells with formation of pseudo-crescents, and trichrome staining revealed tubulo-interstitial fibrosis. Mitochondrial dysfunction in podocytes has been shown to contribute to development of FSGS. Transcriptional profiling at 2 months of age revealed significant enrichment in the oxidative phosphorylation pathway for downregulated genes in the mutant (35 genes, p=1.18 X 10-18). Mutant mice frequently die after 6 months of age, however survivors at 1 year of age have significantly elevated sCr (0.16±0.013 vs 0.122±0.009 mg/dL, p=0.035, n= 5 mut, 10 control).

Conclusion

Our results suggest that regulation of metabolic homeostasis by NuRD is required for proper kidney development and for maintenance of normal glomerular function after birth.

Funding

  • NIDDK Support