Abstract 135: PVN Galphai2 Protein Over Expression Attenuates Dahl Salt Sensitive Hypertension and GNAI2 Polymorphic Variance Represents a Clinical Biomarker of the Salt Sensitivity of Blood Pressure

Abstract

Aim: We hypothesize that a) in the DSS rat, which in contrast to the normotensive DSR rat fails to up regulate PVN Gαi 2 proteins on a high salt intake (Wainford et al, Hypertension 2015), PVN specific Gαi 2 protein over expression will attenuate the development of salt sensitive hypertension (HTN) and, b) SNPs in the GNAI2 gene, which are associated with HTN in Japanese and Italian populations, represent a biomarker of the salt-sensitivity of BP. Methods: Male DSS rats instrumented with a radiotelemetry probe (DSI; PA-C40) received a bilateral PVN shuttle or Gαi 2 expressing lenti-viral vector microinjection (2x10 9 infectious units per ml/60nl/side) and were maintained on a 7-day normal 0.4% (NS) intake for baseline BP prior to 21 day high 4% NaCl (HS) intake. On day 21 rats were sacrificed to assess PVN Gαi 2 protein expression (immunoblotting), plasma NE content (ELISA) or underwent a 5% volume expansion (VE) prior to cardiac perfusion and c-fos IHC to assess PVN neuron activation (N=4/gp/study). SNPs in the GNAI2 gene were examined in GenSalt (N=968) for associations with the salt sensitivity of BP (increase in systolic BP of 5mmHg or greater during HS intake, N=326 are salt sensitive: 172 Female, 154 male). Results: Bilateral lenti-virus increased PVN Gαi 2 protein levels 3 fold (p<0.05) on both NS and HS intake, attenuated HTN (Day 21 HS MAP [mmHg] shuttle 160±3 vs. Gαi 2 144±4, P<0.05), abolished Na + evoked global and renal sympathoexcitation (Day 21 HS plasma NE [nmol/L] shuttle 82±5 vs. Gαi 2 50±4, P<0.05). PVN Gαi 2 over expression increased VE-evoked natriuresis (peak natriuresis (UNaV; [μeq/min] shuttle NS 43±3, shuttle HS 16±3, Gαi 2 HS 31±3, P<0.05) and PVN sympathoinhibitory parvocellular neuron activation (medial parvocellular c-Fos positive cells shuttle NS 67±8, shuttle HS 29±3, Gαi 2 vector HS 48±6, P<0.05). 3 GNAI2 SNPs are present in GenSalt - rs9852677 and rs2282751 did not associate with the salt sensitivity of BP. SNP rs10510755 positively correlated with the salt sensitivity of BP (MAF:6%, Z-score: 1.94, p<0.05) independently of sex. Conclusion: These data suggest a critical role of PVN Gαi 2 proteins in countering the pathophysiology of salt sensitive HTN and that GNAI2 polymorphic variance represents a biomarker of the individual salt sensitivity of BP.