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Abstract: FR-OR075

Mutation of the Furin Cleavage Site in the (Pro)Renin Receptor Attenuates Angiotensin II-Induced Hypertension and Albuminuria

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Ramkumar, Nirupama, University of Utah, Salt Lake City, Utah, United States
  • Stuart, Deborah, University of Utah Health Sciences, Salt Lake City, Utah, United States
  • Wheatley, William, University of Utah, Salt Lake City, Utah, United States
  • Symons, J. David, University of Utah, Salt Lake City, Utah, United States
  • Kohan, Donald E., University of Utah Health Sciences Center, 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 can promote angiotensin-II (Ang-II) formation. Although alterations in plasma sPRR levels have been reported in hypertension, the causal role of sPRR in hypertension is unknown.

Methods

To investigate this, we mutated the furin cleavage site (R276A, R279A) of the PRR using CRISPR/Cas9. Because the gene encoding PRR is on the X-chromosome and male mutant mice are infertile, only male mice were studied.

Results

Mutant mice had markedly lower plasma sPRR levels (control: 16.2 ± 0.3 vs mutant 0.2 ± 0.03 ng/ml). Mutant mice had normal survival and development and no histological renal abnormalities up to 12 months of age. During normal salt intake, no differences in blood pressure, body weight, urinary water or Na+excretion, or acid-base status were observed between control and mutant mice. Compared to controls, mutant mice had an attenuated hypertensive response to 2 weeks of Angiotensin-II infusion (400 ng/kg/min) (Figure 1). Mutant mice also had lower albuminuria (control: 327 ± 114 vs mutant: 58 ± 8 µg/day) at day 7 post Ang-II infusion. No differences in urinary Na+excretion were detected between control and mutant mice after 7 days of Ang-II infusion (control: 33.6 ± 3.1 vs mutant: 35 ± 2.7 µmol/day/gram body weight). Mesentric arteries isolated and studied ex-vivo using isometric tension procedures showed an attenuated vascular response to Ang-II (10-8 M) compared to controls (internal diameter control: 115 ± 7 µm vs mutant 125 ± 8 µm).

Conclusion

These results suggest that sPRR plays a role in Ang-II induced hypertension and renal injury.