Abstract: TH-PO211
Effect of Dual Blockade of Neprilysin and Renin-Angiotensin System in Angiotensin II-Dependent Salt-Sensitive Hypertension
Session Information
- Hypertension and CVD: Basic Research Findings
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Eriguchi, Masahiro, Nara Kenritsu Ika Daigaku, Kashihara, Nara, Japan
- Uemura, Takayuki, Nara Kenritsu Ika Daigaku, Kashihara, Nara, Japan
- Nishimoto, Masatoshi, Nara Kenritsu Ika Daigaku, Kashihara, Nara, Japan
- Tsuruya, Kazuhiko, Nara Kenritsu Ika Daigaku, Kashihara, Nara, Japan
Background
Neprilysin (NEP) is a Zn-metalloprotease whose substrate is brain natriuretic peptide (BNP), but also angiotensin II (Ang II). Interestingly, angiotensin converting enzyme (ACE) is also a Zn-metalloprotease, and both are strongly expressed in the brush border of the proximal tubule. These two proteases are thought to be involved in the regulation of sodium balance by regulating the Intrarenal Ang II by the degradation (NEP) and production (ACE) of Ang II.
Methods
An Ang II-dependent salt-sensitive model was induced by a 4% high-salt diet (HS) after continuous low-dose Ang II infusion for 1 week (300 ng/Kg/min). Blood pressure (BP) and salt sensitivity were examined using Wild-type, NEP KO, renal-ACE KO, and NEP/renal-ACE double-KO mice.
Results
BP of NEP KO mice significantly increased after Ang II infusion (Ang II BP), but the increase in BP 3 days after starting a high-salt diet (Ang II+HS BP) was blunted. (baseline BP: 102 mmHg, Ang II BP: 119 mmHg, Ang II+HS BP: 119 mmHg) On the other hand, in renal-ACE KO mice, no increase in BP was observed in response to Ang II infusion, but BP increased significantly after starting a high-salt diet. (baseline BP: 104 mmHg, Ang II BP: 101 mmHg, Ang II+HS BP: 119 mmHg) At the final observation (Ang II＋HS for 10 days), the BP of NEP/renal-ACE double-KO mice was significantly lower than that of NEP KO, renal-ACE KO, and Wild-type mice. (NEP/renal-ACE double-KO: 122 mmHg, NEP KO: 139 mmHg, renal-ACE KO: 137 mmHg, Wild-type: 148 mmHg) Under 1-week Ang II infusion, 3-h urinary Na excretion in response to intraperitoneal saline challenge was significantly increased in NEP/renal ACE double-KO mice compared with wild-type mice. (NEP/renal-ACE double-KO: 0.193 mEq, NEP KO: 0.171 mEq, renal-ACE KO: 0.164 mEq, Wild-type: 0.113 mEq) Also, intrarenal Ang II concentration was elevated in NEP KO mice, whereas the increase in intrarenal Ang II was suppressed in renal-ACE KO and NEP/renal-ACE double-KO mice. (NEP/renal-ACE double-KO: 199 fmol/g kidney weight, NEP KO: 448 fmol/g, renal-ACE KO: 210 fmol/g, Wild-type: 294 fmol/g)
Conclusion
Dual blockade of NEP and renin-angiotensin system was shown to have a complementary anti-hypertensive effect by BNP-induced natriuresis and suppressing salt sensitivity due to an increase in intrarenal Ang II concentration.