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

SNP's in the GNAI2 gene increase the hypertension risk in Italian & Japanese populations. We have shown that CNS Gαi 2 protein pathways mediate the renal sympathoinhibition and natriuresis evoked by α 2 ‐adrenoceptor activation in‐vivo . Therefore, we examined the role of CNS Gαi 2 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) Gαi 2 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 Gαi 2 down‐regulation caused renal nerve‐dependent sodium retention (24h Na+ balance [meq]; Scr + HS 0.3±0.1, Gαi 2 + HS 2.9±0.3*, Gαi 2 RDNX + HS 0.8±0.4τ), global sympathoexcitation (plasma NE [nmol/L] Scr + HS 49±5, Gαi 2 + HS 98±8*, Gα i2 RDNX + HS 73±5 τ ) and hypertension (MAP [mmHg] Scr + HS 128±3, Gαi 2 + HS 147±3*, Gαi 2 RDNX + HS 132±2 τ ). In DSS rats, chronic brain Gαi 2 ODN infusion exacerbated salt‐induced hypertension (MAP [mmHg] Scr + HS 164±3 vs. Gαi 2 + HS 183±4*), sodium retention and global sympathoexcitation (plasma NE [nmol/L] Scr + HS 87±6 vs. Gαi 2 + HS 115±8). In salt‐resistant, but not salt‐sensitive animals, PVN Gαi 2 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, τ p<0.05 vs. Gαi 2 + HS; HL107330