Abstract 073: The Absence Of Renal Angiotensin-converting Enzyme Prevents Salt Sensitive Hypertension
We previously showed that the renal ACE/angiotensin (Ang) II pathway is a master switch for sodium transport along the nephron. Further, we hypothesized that this pathway plays a key role in the development of salt sensitive (SS) hypertension. To test this, wild-type mice (WT) and mice lacking renal ACE (ACE 10/10) were exposed to post-L-NAME hypertension: L-NAME, 4 weeks → Washout, 1 week → high salt diet (HS, NaCl 4%), 3 weeks. In WT mice, L-NAME increased systolic blood pressure (SBP) from 110±2 to 135±3 mmHg (p<0.01; n=12). SBP then returned to baseline during the washout and increased again in response to the HS diet (131±3 mmHg; p<0.01). Thus, WT mice, previously salt resistant, become salt sensitive. Remarkably, ACE 10/10 mice, despite being equally hypertensive during the L-NAME phase, DID NOT develop salt sensitivity. At the end of HS phase, the ACE 10/10 SBP was 106±5 mmHg (NS). While baseline renal Ang II levels were similar (by IHC), HS diet induced a greater renal Ang II accumulation in WT vs. ACE 10/10 (26±2 vs. 13±2 % of positive staining/area; p<0.01). After 24 hr of sodium load, WT mice had a positive sodium balance (1841±360 μmol/day/100g b.w) that was later corrected at the expense of hypertension. In contrast, ACE 10/10 mice showed an enhanced natriuretic response that resulted in less sodium accumulation (604±300 μmol/day/100g b.w; p<0.01 vs. WT) and the absence of hypertension. In response to the salt load, glomerular filtration rate (GFR) was higher in ACE 10/10 compared to WT (1595±49 vs. 1451±49 μl/min/100g b.w after 24 h; p<0.01). Eventually, GFR returned to baseline values in both groups (WT: 1408±37; ACE10/10: 1393±42 μl/min/100g b.w.; NS). The analysis of key sodium transporters revealed that the natriuretic response of ACE 10/10 was associated with lower phosphorylated (p) NKCC2, pNCC and less ENaC α subunit abundance (33%, 31% and 25% reduction vs. WT, respectively; p<0.01). Furthermore, after 7 days of HS diet, ENaCα remained lower in ACE 10/10 vs. WT (31% reduction; p<0.01). These data indicate that renal ACE plays an important modulatory role in the GFR and sodium transporter responses that induce salt sensitivity.
Author Disclosures: J.F. Giani: None. T. Janjulia: None. J. Han: None. B. Rodriguez-Iturbe: None. K.E. Bernstein: None. A.A. McDonough: None. R.A. Gonzalez-Villalobos: None.
- © 2014 by American Heart Association, Inc.