The GNAI2 gene ‐ a candidate biomarker of hypertension that determines salt‐resistance vs. salt‐sensitivity in rat models

Abstract

SNP's in the GNAI2 gene increase the hypertension risk in Italian & Japanese populations. We have shown that CNS Gαi2 protein pathways mediate the renal sympathoinhibition and natriuresis evoked by α2‐adrenoceptor activation in‐vivo. Therefore, we examined the role of CNS Gαi2 proteins in the regulation of fluid & electrolyte homeostasis and MAP in response to high salt intake in intact and renal denervated (RDNX) rats. Following 21‐day high salt (HS) intake (8% NaCl diet) we observed a site specific increase in hypothalamic paraventricular nucleus (PVN) Gαi2 proteins in Sprauge‐Dawley (SD) and Dahl Salt‐Resistant (5.8, & 7.6 fold respectively, P<0.05), but not Dahl Salt‐Sensitive (DSS) rats. In SD rats, oligodeoxynucleotide (ODN)‐mediated Gαi2 down‐regulation caused renal nerve‐dependent sodium retention (24h Na+ balance [meq]; Scr + HS 0.3±0.1, Gαi2 + HS 2.9±0.3*, Gαi2 RDNX + HS 0.8±0.4τ), global sympathoexcitation (plasma NE [nmol/L] Scr + HS 49±5, Gαi2 + HS 98±8*, Gαi2 RDNX + HS 73±5τ) and hypertension (MAP [mmHg] Scr + HS 128±3, Gαi2 + HS 147±3*, Gαi2 RDNX + HS 132±2τ). In DSS rats, chronic brain Gαi2 ODN infusion exacerbated salt‐induced hypertension (MAP [mmHg] Scr + HS 164±3 vs. Gαi2 + HS 183±4*), sodium retention and global sympathoexcitation (plasma NE [nmol/L] Scr + HS 87±6 vs. Gαi2 + HS 115±8). In salt‐resistant, but not salt‐sensitive animals, PVN Gαi2 proteins are up‐regulated to mediate endogenous anti‐hypertensive sympathoinhibitory mechanisms to maintain fluid & electrolyte homeostasis and normotension during HS challenge; this may reflect a potential mechanism by which GNAI2 SNP's increase the risk of hypertension in human populations. *p<0.05 vs. Scr + HS, τp<0.05 vs. Gαi2 + HS; HL107330