Abstract 26: PVN GaI2 Subunit Proteins - The Key to a Salt-resistant Phenotype?

Abstract

Aim: Endogenous up-regulation of PVN Gαi 2 proteins facilitates sympathoinhibition and normotension during chronic Na + challenge in Sprague-Dawley rats via a renal-nerve dependent mechanism. Therefore, we examined the role of PVN Gαi 2 proteins in MAP regulation during high salt-intake in intact and renal denervated (RDNX) Dahl salt-resistant (DSR) & salt-sensitive (DSS) rats and naive Brown Norway (BN) and DSSBN8 congenic rats. Methods: Sham (S) or RDNX DSR & DSS rats receiving a continuous i.c.v. infusion of a scrambled (SCR) or Gαi 2 oligodeoxynucleotide (25 μg/day), and naïve BN and DSSBN8 rats, were fed a 21-day normal 0.4% (NS) or high 8% NaCl (HS) diet. MAP was recorded continuously by radiotelemetry and Na + homeostasis was assessed via metabolic balance studies. On day-21 plasma norepinephrine (NE), autonomic function and PVN Gαi 2 protein levels were determined (N=6/gp). Results: HS-intake did not alter MAP, suppressed plasma NE (P<0.05), and evoked a site-specific increase in PVN Gαi 2 protein levels in BN & DSR (4.8 and 4.5-fold respectively, P<0.05), but not DSS rats. In DSR rats Gαi 2 down-regulation evoked rapid renal nerve-dependent hypertension (MAP [mmHg] Day 4 HS S 121±2* vs RDNX 101±2, Day 21 HS S 127±2* vs RDNX 101±1), Na + retention and sympathoexcitation (plasma NE [nmol/L] S 87±7* vs RDNX 37±3, peak ΔMAP to chlorisondamine [mmHg] S -68±4* vs RDNX -37±3). In DSS rats, Gαi 2 down-regulation exacerbated salt-induced hypertension (MAP [mmHg] Day 4 HS S 148±5* vs RDNX 133±4, Day 21 HS S 175±4* vs RDNX 145±3), Na + retention, and sympathoexcitation (plasma NE [nmol/L] S 118±9* vs RDNX 88±6) in a renal nerve dependent manner. DSSBN8 rats exhibited PVN specific Gαi 2 protein up-regulation, attenuated hypertension (MAP [mmHg] Day 21 DSSBN8 HS 142±2 τ , DSS HS 155±4), Na + retention and global sympathoexcitation (plasma NE [nmol/L] DSSBN8 HS 52±4 τ , DSS HS 87±6). *p<0.05 vs RDNX + HS, τ p<0.05 vs DSS. Conclusion: PVN Gαi 2 protein-gated pathways represent a conserved central molecular pathway mediating sympathoinhibitory renal-nerve dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. Owing to SNP’s in the human GNAI2 gene (which encodes Gαi 2 ) correlating with hypertension our findings have translational implications.