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Kidney Week

Abstract: SA-PO975

Loss of Soluble (Pro) Renin Receptor Attenuates Adenine Induced Kidney Disease

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Ramkumar, Nirupama, University of Utah Health, Salt Lake City, Utah, United States
  • Hu, Chunyan, University of Utah Health, Salt Lake City, Utah, United States
  • Stuart, Deborah, University of Utah Health, Salt Lake City, Utah, United States
Background

Cleavage of the extra-cellular domain of the (pro)renin receptor (PRR) yields a soluble fragment termed soluble PRR (sPRR). Elevated plasma sPRR levels have been described in patients with kidney disease and correlates with the stage of kidney disease. We previously demonstrated that loss of sPRR attenuated angiotensin-II induced hypertension and kidney injury. To further characterize the role of sPRR in chronic kidney disease and fibrosis, we used adenine diet to induce kidney disease in control and mutant mice with loss of sPRR.

Methods

Using CRISPR-Cas9, we developed a mouse model with site-directed mutagenesis of the PRR cleavage site. Male, 3-month old, mutant sPRR mice and littermate controls were treated with adenine diet (alternating between 0.25% and 0.15%) for 8 weeks. Only male mice were studied as the PRR gene is on the X-chromosome.

Results

Compared to controls, male mutant sPRR mice had markedly lower plasma sPRR levels (control: 21.5 ± 2.5 vs mutant 0.2 ± 0.03 ng/ml). Metabolic balance studies at the end of the study showed similar food intake and body weight between the two groups although water intake (control: 6.9 ± 0.4 vs mutant: 3.6 ± 0.3 ml/24 hrs, p<0.001) and urine volume (control: 5.9 ± 0.2 vs mutant: 2.9 ± 0.5 ml/24 hrs, p=0.001) was significantly lower in mutant sPRR mice. Mutant sPRR mice also had lower BUN (control: 67.4 ± 3.1 vs mutant: 42.9 ± 2.2 mg/dl p<0.01), serum creatinine (control: 1.59 ± 0.1 vs mutant: 1.21 ± 0.04 mg/dl, p<0.01) and urinary excretion of albumin (control: 92.6 ± 7.5 vs mutant: 47.1 ± 5.7 ug/day, p<0.01) and kidney injury molecule (KIM-1) (control:155 ± 10 vs 75 ± 5 ng/day, p<0.01) compared to controls. Renal histology demonstrated significant tubular and interstitial injury with minimal glomerulosclerosis in control mice treated with adenine diet while injury was significantly reduced in mutant sPRR mice. Bulk RNA sequencing of whole kidney lysates showed 135 upregulated genes and 167 downregulated genes with pathway analyses suggesting downregulation of Jak/Stat, Mapk and TGF-b signaling in the mutant sPRR mice.

Conclusion

Loss of sPRR attenuates adenine diet induced kidney disease likely via downregulation of inflammatory and fibrotic signaling pathways. Studies to delineate how sPRR mediates renal tubular injury and fibrosis are currently ongoing.