Abstract: SA-OR050

Conditional Ablation of the Prorenin Receptor (PRR) in Nephron Progenitor Cells (NPCs) Results in Developmental Programming of Hypertension

Session Information

Category: Developmental Biology and Inherited Kidney Diseases

  • 403 Pediatric Nephrology

Authors

  • Song, Renfang, Tulane University, New Orleans, Louisiana, United States
  • Janssen, Adam T., Tulane University, New Orleans, Louisiana, United States
  • Kidd, Laura R., Tulane University, New Orleans, Louisiana, United States
  • Yosypiv, Ihor V., Tulane University, New Orleans, Louisiana, United States
Background

The PRR is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump V-ATPase. Previously, we demonstrated that conditional ablation of the PRR in Six2+ NPCs in mice (cKO) causes reduced congenital nephron endowment and early neonatal death (Song et al., 2016).

Methods

Here, we: 1) Investigated PRR-regulated genes and pathways in Six2+ NPCs FACS-isolated from cKO and control (Co) kidneys on embryonic day E15.5 (n=3 pooled samples/genotype) using whole-genome-based analysis of gene expression; 2) Tested whether reduced PRR gene dosage in heterozygous Six2PRR+/- mice (Het) is associated with development of hypertension during later life; and 3) Tested the hypothesis that soluble PRR (sPRR), PRR cleavage product generated subcellularly and secreted into the urine by renal tubular cells, can contribute to BP programming in Het mice.

Results

Top 10 genes downregulated in cKO included Hoxb8, Mspt, Mdfi and Gpc2. The functional groups of differentially expressed genes within the altered gene set in cKO mice included genes involved in embryonic development, tissue/cell morphology, cellular assembly and organization, cell death and survival. While the number of glomeruli per kidney section was reduced at 2 months of age (69±4.0 vs. 178±4.9, p<0.001), conscious tail-cuff mean (95.5±2.8 vs. 70.4±3.8, p<0.01), systolic (143±5.3 vs. 113±6.5, p<0.01) and diastolic (67±4.5 vs. 51±4.0, p<0.05) arterial blood pressure was increased in Het compared with Co mice. Electron microscopy showed segmental thickening of the GBM with focal podocyte foot process effacement in Het mice. Urine sPRR levels measured by ELISA at 2 months of age were increased in Het compared to Co mice (262±28 vs. 146±13 pg/ml, p<0.01).

Conclusion

These data demonstrate that NPC PRR performs essential functions during nephrogenesis via control of hierarchy of genes that regulate critical cellular processes. Reduced nephron endowment, glomerular injury and augmented urine sPRR likely contribute to programming of hypertension in Het mice.