Hypothalamic PVN Gαi2 protein‐mediated regulation of renal NE turnover and sodium homeostasis: implications for the pathophysiology of salt‐sensitive hypertension (860.23)

Abstract

Aim: These studies examined the direct role of PVN Gαi2 proteins, which are up‐regulated during high‐salt intake in Sprague‐Dawley (SD) rats, in the regulation of water & electrolyte homeostasis, MAP and CNS/renal norepinephrine (NE) levels during high salt‐intake.Methods: Groups of male SD rats received a bilateral PVN infusion of a scrambled (S) or Gαi2 oligodeoxynucleotide (ODN‐300ng/side/day) and a 7‐day normal 0.4% (NS) or high 8% NaCl (HS) diet. On day‐7 24h Na+ balance was assessed. In sub‐groups MAP, estimated blood volume (EBV), estimated plasma volume (EPV), plasma NE levels and PVN and kidney NE turnover were assessed (N=6/gp/study).Results: In S infused rats HS did not alter sodium homeostasis (24h Na+ balance [meq] NS 0.7±0.3 vs HS 0.9±0.3), MAP (MAP [mmHg] NS 126±3 vs HS 127±3) or EBV and EPV. In S infused rats HS intake suppressed plasma NE content (plasma NE [nmol/L] NS 72±4 vs HS 40±5, P<0.05), kidney NE content (NE [pg/mg] NS 586±36 vs HS 496±31, P<0.05) and NE turnover in the PVN. HS intake in rats receiving a Gαi2 infusion evoked sodium retention (24h Na+ balance [meq] NS 0.6±0.2 vs HS 2.5±0.4 P<0.05), hypertension (MAP [mmHg] NS 127±3 vs HS 146±4, P<0.05) and increased blood and plasma volume (EPV [ml] NS 10.9±0.4 vs HS 11.8±0.4, P<0.05; EBV [ml] NS 21.1±0.5 vs HS 22.4±0.3, P<0.05). In Gαi2 infused rats HS intake increased plasma NE content (plasma NE (NE [nmol/L]; NS 67±7 vs HS 105±11, P<0.05), kidney NE content (NE [pg/mg] NS 614±48 vs HS 823±59, P<0.05) and kidney NE turnover (NE turnover rate [pg/mg/hr] NS 7.5±0.6 vs HS 20.3±1, P<0.05) while suppressing PVN NE turnover.Conclusion: Impairment of PVN Gαi2 signal transduction during high salt‐intake results in dysregulation of renal NE content and turnover. This imbalance likely drives sodium & fluid retention stimulating the development of hypertension. These data highlight the interaction between the CNS and kidney, and the role of the sympathetic nervous system, in the long‐term regulation of MAP.Grant Funding Source: Support by R01HL107330 & K02HL112718A1