Adrenergic regulation of the NCC in the development and maintenance of Dahl Salt‐Sensitive Hypertension occurs via a WNK/SPAK/OxSR1 pathway

Abstract

BackgroundDietary sodium intake significantly influences blood pressure (BP) regulation, as increased sodium reabsorption is a well‐established precursor of hypertension risk. In a subset of individuals that demonstrate the salt sensitivity of BP, increased dietary sodium intake evokes significant increases in BP and contributes to the development of salt‐sensitive hypertension (SSH). Studies suggest that excessive Sympathetic Nervous System (SNS) release of norepinephrine (NE) stimulates activity of the sodium chloride cotransporter (NCC) via synergistic α1 or β adrenergic receptor pathways to drive SSH.HypothesisExcessive SNS release of NE influences NCC activity via an α1‐adrenoceptor gated pathway that relies upon WNK/SPAK/OxSR1 signaling to drive the development of Dahl SSH.MethodsGroups of naïve Dahl Salt Sensitive (DSS) rats, Dahl Salt Resistant (DSR), DSS rats receiving a continuous subcutaneous (s.c.) terazosin (10 mg/kg/day), or s.c. propranolol (10 mg/kg/day) infusion were fed a normal salt (NS, 0.6% NaCl) or high salt (HS, 4% NaCl) diet for 21 days respectively. On day 21 basal MAP and NCC activity (peak natriuresis to iv hydrochlorothiazide (HCTZ; 2mg/kg) infusion) were assessed. NCC, phosphoNCC, WNK1, SPAK, and OxSR1 expression were assayed via immunoblotting (N=6/gp). Additional groups of DSS rats were fed a 42 day HS diet. On day 21, rats were given s.c. saline or s.c. terazosin (10 mg/kg/day). On day 42, measurements were taken as described previously (N=6/gp).ResultsDSR rats maintain normal BP when fed a 21 day HS diet and suppress NCC activity, expression, and phosphorylation compared to rats on a NS diet. DSS rats develop SSH when fed a 21 day HS diet and exhibit increases in NCC activity, expression, and phosphorylation compared to rats on a NS diet. Chronic α1‐adrenoceptor antagonism (confirmed pharmacologically) using terazosin attenuates SSH, reduces NCC activity, expression, and phosphorylation in rats on a HS diet. β‐adrenoceptor antagonism using propranolol fails to attenuate SSH or influence NCC activity. Critically, α1‐antagonism reduces BP and NCC activity and expression in DSS rats with established SSH.ConclusionSalt resistance in DSR rats is marked by dietary sodium‐evoked suppression of NCC activity and expression. Salt sensitivity in DSS rats is driven in part by a failure to suppress NCC activity or expression and contributes to the development of SSH. α1‐adreoceptor antagonism attenuates both the development and maintenance of SSH in DSS rats by evoking suppression of NCC activity and expression. Collectively our findings suggest that excessive SNS release of NE influences NCC activity via α1‐adrenoceptor pathway to drive sodium reabsorption and the development of SSH.Support or Funding InformationThis work was supported by NIH R56 AG057687, R01 HL139867, R01 HL141406, R01 HL107330 and K02 HL112718 and AHA 16MM32090001 and 17GRNT33670023 to R.D.W., NIH F31 DK116501 to A.A.F., ASN Foundation for Kidney Research Pre‐Doctoral Fellowship award and APS William Townsend Porter Physiology Development Fellowship award to F.P. Dietary Salt Intake MAP (mmHg) Peak ΔUNaV to HCTZ (μeq/min) NCC Expression (Fold Change) Total pNCCT53 (Fold Change) WNK1 Expression (Fold Change) SPAK Expression (Fold Change) OxSR1 Expression (Fold Change) Naïve DSR rat 21‐day NS 129 ± 3 10.5 ± 1.2 1 ± 0.06 1 ± 0.14 1 ± 0.05 1 ± 0.11 1 ± 0.08 HS 131 ± 2 8.5 ± 1.0 * 0.34 ± 0.04 * 0.23 ± 0.03 * 0.76 ± 0.08 0.83 ± 0.15 0.49 ± 0.05 * Naïve DSS rat 21‐day NS 127 ± 3 9.4 ± 0.6 1 ± 0.14 1 ± 0.17 1 ± 0.08 1 ± 0.11 1 ± 0.05 HS 162 ± 4 * 11.4 ± 0.4 * 1.09 ± 0.14 1.05 ± 0.17 1.04 ± 0.12 0.96 ± 0.15 0.96 ± 0.06 DSS rat 21‐day sc Terazosin HS 143 ± 3 # 5.9 ± 0.6 # 0.25 ± 0.13 # 0.42 ± 0.20 # 0.25 ± 0.08 # 0.30 ± 0.08 # 0.71 ± 0.01 # DSS rat 21‐day sc Propanolol HS 157 ± 4 10.4 ± 0.6 0.88 ± 0.04 0.95 ± 0.06 0.99 ± 0.01 0.37 ± 0.06 # 1.09 ± 0.01 DSS rat 42‐day sc Saline HS 207 ± 5 14.4 ± 0.6 1 ± 0.10 1 ± 0.20 1 ± 0.19 1 ± 0.19 1 ± 0.05 DSS rat 42‐day sc Terazosin HS 191 ± 3 Φ 9.3 ± 2.0 Φ 0.69 ± 0.08 Φ 0.42 ± 0.15 Φ 0.48 ± 0.09 Φ 0.97 ± 0.11 0.88 ± 0.09 *p<0.05 vs. respective naive Normal Salt (NS, 0.6% NaCl) group; #p<0.05 vs. naive DSS 21 Day High Salt (HS, 4% NaCl) group; Φp<0.05 vs. 42 day subcutaneous (sc) saline group.