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Abstract: PO2144

Loss of Soluble (Pro)renin Receptor Attenuates DOCA-Salt Hypertension

Session Information

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 ± 0.33.6 ± 0.1
Water intake (ml/day) *13.2 ± 1.48.8 ± 0.5
Urine volume (ml/day) *10.4 ± 1.06.4 ± 0.5
Body weight (g)*30.9 ± 1.525.0 ± 0.3
UNaV (μmol/day)3279 ± 1242865 ± 282
UKV (μmol/day) *421 ± 29335 ± 32
Urine albumin (μg/day)77 ± 3362 ± 36
   
   

* P value <0.05 by T-test

Funding

  • Private Foundation Support