Abstract 102: Renal Mechanisms of Blood Pressure Homeostasis and Salt Sensitivity by Collectrin
Collectrin (Tmem27), an ACE-2 homologue and a chaperone of amino acid transporters, is expressed in the endothelium and renal epithelia, including the proximal tubules and collecting duct. We previously reported that collectrin-deficient (KO) mice exhibit hypertension (HTN) at baseline and augmented salt-sensitivity associated with impaired endothelial-dependent relaxation and a rightward shift of the pressure-natriuresis relationship. To determine the effect of renal vs. extra-renal collectrin on blood pressure (BP) regulation, we performed renal cross-transplantation studies (at the Duke O’Brien Center), then treated with normal salt (NSD) and high salt (HSD) diets, in the following groups (n = 3-5/group): 1) wild-type (WT) mice with WT kidney (WT WT), 2) collectrin KO mice with WT kidney (WT KO), and 3) WT mice with collectrin KO kidney (KO WT). Collectrin KO WT group displayed a trend towards higher baseline systolic BP (SBP, mmHg); however, under HSD, collectrin KO WT had significantly higher SBP (WT WT 148.9, WT KO 151.6, KO WT 168.6, p = 0.037).
To determine the renal endothelial and epithelial contribution of collectrin in BP regulation, we assessed renal blood flow (RBF) by contrast-enhanced ultrasound and renal sodium transporters and channels by immunoblotting. KO mice displayed significantly reduced total, cortical and medullary RBF under both NSD and HSD (n ≥ 11 each, p ≤ 0.01). Moreover, at baseline, compared to WT mice (n = 4), KO mice (n = 5) displayed significantly elevated abundance of NHE3 (p = 0.002), activated NCC (NCC-pS71) (p = 0.004) and ENaC alpha (p = 0.03).
We next conducted a candidate gene association study in the HyperGen cohort (1,270 white participants, 50% men), using intronic SNPs in the ACE2, TMEM27 and CA5BP1 genes on the X chromosome. Only 2 SNPs, rs6629114 and rs41492646, both of TMEM27 and in perfect linkage disequilibrium (r2=1.0), were associated with diastolic BP (DBP). Meta-analysis of men and women showed this was statistically significant, (p=0.04 for both), with stronger effects in men (p=0.028).
In conclusion, deletion of collectrin alters renal hemodynamics and epithelial sodium handling to favor sodium reabsorption. Collectrin is associated with DBP in human subjects.
Author Disclosures: P. Chu: None. J.C. Gigliotti: None. S. Cechova: None. F. Chan: None. D.L. Ralph: None. N. Franceschini: None. A.A. McDonough: None. T.H. Le: None.
- © 2015 by American Heart Association, Inc.