Abstract: SA-PO309
Deletion of NuRD Component MTA2 in Nephron Progenitors Results in Renal Hypoplasia and Focal Segmental Glomerulosclerosis
Session Information
- Cellular Crosstalk in Glomerular Diseases - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
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