Abstract: PO2144
Loss of Soluble (Pro)renin Receptor Attenuates DOCA-Salt Hypertension
Session Information
- Mechanisms of Kidney and Vascular Disease
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Ramkumar, Nirupama, University of Utah Health, Salt Lake City, Utah, United States
- Stuart, Deborah, University of Utah Health, Salt Lake City, Utah, United States
- Peterson, Caitlin S., University of Utah Health, Salt Lake City, Utah, United States
- Wheatley, William, University of Utah Health, Salt Lake City, Utah, United States
- Kohan, Donald E., 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 (sPRR), which may be involved in mediating hypertension. We recently developed a mouse model with mutation in the cleavage site of the PRR using CRISPR/Cas9 such that sPRR is not generated and showed that absence of sPRR attenuated angiotensin-II induced hypertension and kidney damage. In this study, we examined if sPRR alters blood pressure (BP) in angiotensin-II independent hypertension using deoxycorticosterone acetate (DOCA)-salt treatment.
Methods
Mutant sPRR mice and littermate controls were treated with DOCA (50 mg/kg) and high Na+ diet for 3 weeks. BP was monitored by radio-telemetry and metabolic balance studies performed on Day 17-18 of DOCA-salt treatment. 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) and baseline BP (systolic control: 122 ± 3 vs mutant 114 ± 3; diastolic control: 94 ± 5 vs mutant 82 ± 3 mm Hg). BP remained low in mutant sPRR mice relative to controls following 12 days of DOCA-salt treatment (systolic control: 141 ± 2 vs mutant 132 ± 5; diastolic control: 110 ± 4 vs mutant 95 ± 5 mm Hg). Mutant sPRR mice had lower body weight but similar food intake and urinary albumin excretion compared to controls (Table 1). Mutant mice had lower urine volume, water intake and urinary K+ but not Na+ excretion. No differences in renal histology were noted between control and mutant sPRR mice.
Conclusion
Loss of sPRR attenuates DOCA-salt mediated hypertension.The mechanisms by which sPRR might regulate BP and water/Na+ homeostasis in DOCA-salt hypertension are currently being investigated.
Table 1
| Control (N=6) | Mutant sPRR (N=7) | |
| Food intake (g/day) | 4.0 ± 0.3 | 3.6 ± 0.1 |
| Water intake (ml/day) * | 13.2 ± 1.4 | 8.8 ± 0.5 |
| Urine volume (ml/day) * | 10.4 ± 1.0 | 6.4 ± 0.5 |
| Body weight (g)* | 30.9 ± 1.5 | 25.0 ± 0.3 |
| UNaV (μmol/day) | 3279 ± 124 | 2865 ± 282 |
| UKV (μmol/day) * | 421 ± 29 | 335 ± 32 |
| Urine albumin (μg/day) | 77 ± 33 | 62 ± 36 |
* P value <0.05 by T-test
Funding
- Private Foundation Support