OS 29-04 SYMPATHETIC NERVOUS SYSTEM REGULATION OF THE RENAL NCC AND BLOOD PRESSURE DURING HIGH DIETARY SALT INTAKE

Abstract

Objective: These studies tested the hypothesis that the SNS release of norepinephrine modulates NCC activity via a WNK1 mechanism to contribute to the pathophysiology of salt-sensitive hypertension in rats. Design and Method: Male Sprague-Dawley (SD) rats receiving a continuous s.c. saline or NE (600 ng/min) infusion or naïve Dahl Salt-Resistant (DSR) and Dahl Salt-Sensitive (DSS) rats were fed a 0.6% (NS) or 8% NaCl (HS) diet for 14 or 21 days respectively (N = 6/group). On day 14 (SD) or 21 (DSR & DSS) MAP, plasma NE content and NCC activity (peak natriuresis to iv hydrochlorothiazide (HCTZ; 2 mg/kg) infusion)), was assessed. Kidney cortical tissue was collected for immunoblotting of NCC, STE-20 Alanine/Proline kinase (SPAK), oxidative stress response-1 (OxSR1) and WNK1 (normalized to beta-actin). Results: Salt-resistant SD & DSR rats exhibit HS evoked suppression of plasma NE and NCC expression and activity. In contrast the DSS rat exhibits hypertension, increased plasma NE and a failure to suppress NCC expression and activity during HS-intake. NE infusion in the SD rat resulted in the development of the salt-sensitive hypertension and a failure of HS to suppress NCC activity and expression. In SD & DSR rats HS evoked down regulation of the protein levels of NCC regulatory kinases SPAK, OxSR1 and WNK1. Further, in the DSR we observed significantly reduced endogenous WNK1 levels on NS intake vs SD and DSS phenotypes (P < 0.05). In contrast, in salt sensitive animals (DSS & sc NE infused SD) we observed no change in NCC regulatory kinase protein expression following HS intake. Conclusions: These data provide new mechanistic insight into the impact of the sympathetic nervous system on the kidney in hypertension and support the hypothesis that cross-talk between increased dietary salt intake and elevated SNS release of NE specifically modulates NCC activity to contribute to the pathophysiology of salt-sensitive hypertension.