High Dietary Salt Intake Drives Sympathetically Mediated Alpha‐1 Adrenoceptor Regulation of NCC to Increase Renal Sodium Retention and Blood Pressure via an OXSR1 Dependent Pathway

Background Acute studies have suggested that sympathetic nervous system (SNS) release of norepinephrine (NE) mediates upregulation of the sodium chloride cotransporter (NCC) via synergistic α1 and β adrenergic receptor pathways. Moreover, recent data suggests a key role of oxidative stress responsive 1 (OXSR1), in NCC regulation. Hypothesis Norepinephrine (NE) activates an α1 adrenoceptor pathway that is dependent on OXSR1 to mediate increases in NCC activity that drive the development of salt sensitive hypertension (HTN). Methods Male Sprague‐Dawley (SD) rats receiving a continuous s.c. saline or NE (600ng/min) infusion were fed a 0.6% (NS) or 4% NaCl (HS) diet for 14 days respectively. Separate groups of NE infused SD rats were given terazosin (10mg/kg/day; s.c.) and a NS or HS diet for 14‐days. An OXSR1 targeted lentivirus was injected in the kidneys of NE infused SD rats prior to a 14 day HS diet. On day 14 basal MAP, NCC activity (peak natriuresis to iv hydrochlorothiazide (HCTZ; 2mg/kg) infusion) and peak MAP change in response to ganglionic blockade (iv hexamethonium; 30mg/kg) were assessed. NCC expression, phosphoNCC, and OXSR1 levels were assayed via immunoblotting (N=4/gp). Results SD rats remain normotensive when fed a high salt diet and NCC expression and activity is downregulated. NE infusion however, inhibits the NCC downregulation associated with HS intake and evokes salt sensitive HTN. Use of an α1‐adrenoceptor antagonist in NE infused SD rats abolishes salt sensitive HTN and downregulates NCC activity. Significantly, lentiviral knockdown of OXSR1 (confirmed by immunoblot) also eliminates salt sensitive HTN in a similar fashion. Furthermore, ganglionic blockade did not produce any observable differences in NE infused rats on HS or NS that were treated or not treated with the α1‐adrenoceptor antagonist or lentivirus. Conclusion Our data reveals that SNS release of NE can modulate NCC activity via an α 1 ‐adrenoceptor pathway to prevent dietary evoked salt sensitive HTN. Remarkably, both OXSR1 knockdown and α1‐adreoceptor antagonism reverse salt sensitive HTN. As a theoretical model, the SNS release of NE activates a linear α1‐adreoceptor pathway that stimulates OXSR1 mediated regulation of NCC. The PATHWAY‐2 Trail implicates sodium retention as a driver of resistant HTN suggesting that α1‐adreoceptor antagonism and OXSR1 blockade may represent novel therapeutic targets for HTN. Support or Funding Information This work was supported by NIH grants R01HL107330 and K02HL112718 and AHA grants 16MM32090001 and AHA17GRNT3367002 to RDW and NIH grant F31DK116501 to AAF. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .