Cross‐talk Between Dietary Salt Intake And Norepinephrine In The Regulation Of Renal NCC Activity And Blood Pressure
Authors: Wainford Richard David , Ruan Qiu Ting , Walsh Kathryn Rose 
Published: November 2023

AimThese studies tested the hypothesis that cross‐talk between dietary salt intake and norepinephrine (NE) modulates NCC activity to contribute to the pathophysiology of salt‐sensitive hypertension.MethodsMale Sprague‐Dawley (SD) rats receiving a continuous s.c. saline or NE (600ng/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; 2mg/kg infusion), was assessed. Kidney cortical tissue was collected for qRT‐PCR analysis (Sybr green) of renal sodium transporters (normalized to b‐actin) and for immunoblotting of NCC, STE‐20 Alanine/Proline kinase (SPAK), oxidative stress response‐1 (OxSR1) and WNK1 (normalized to b‐actin).ResultsSalt‐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 (modeling sympathoexcitation observed in DSS rat) resulted in the development of the salt‐sensitive hypertension and a failure of HS to suppress NCC activity and expression. mRNA analysis revealed HS down regulated NCC and ENaC (approximately 2‐fold, P<0.05) and that NE infusion selectively abolished HS evoked NCC, but not ENaC mRNA, down regulation. 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.ConclusionThese data support the hypothesis that cross‐talk between increased dietary salt intake and elevated NE levels specifically modulates NCC activity to contribute to the pathophysiology of salt‐sensitive hypertension. In salt‐resistant models HS evoked suppression of sympathetically mediated NE release decreases NCC activity via down regulation of multiple NCC regulatory kinases. In contrast, in hypertensive salt‐sensitive models featuring excess NE (sympathoexcitation), NCC activity is maintained by a failure of HS to suppress SPAK, OxSR1 and WNK1. Our finding of a reduced basal level of WNK1 in the DSR rat suggests a central role of WNK1 in NCC regulation. These data highlight a direct role of NE on NCC function during HS intake and provide new mechanistic insight into the impact of the sympathetic nervous system on the kidney in hypertension.Support or Funding InformationNHLBI R01HL107730, K02HL1127182

sc Saline
DSR
DSS
sc NE

NS
HS
NS
HS
NS
HS
NS
HS

MAP (mmHg)
124±2
124±1
129±3
131±2
138±6
166±6*
151±3* τ
171±4*

Plasma NE (nmol/L)
51 ±4
33±5*
48±6
29±4*
47+6
88±4*τ
99±5
113±9*≠

Peak ΔUNaV to HCTZ (μeq/min)
8.7±0.3
7.2±0.7*
10.5±1.2
8.5±1.0*
10.7±1.2
10.4±1.3τ
11.1±1.11
10.8±0.4≠

NCC (ODU/mm2)
1.7±0.4
1.1±0.3*
1.2±0.3
0.5±0.01*
2.4±0.75
2.9±0.5τ
1.9±0.3
2.9±0.9≠

SPAK (ODU/mm2)
1.9±0.3
0.8±0.1*
2.42±1
0.7±0.2*
4.2±1.6
4.3±0.6τ
6.4±1.5
7.34±1.5≠

OxSR1 (ODU/mm2)
6.7±1.8
3.9±1.6*
2.2±0.6
1.1±0.3*
11.2±4.5
11.4±2.7τ
12.7±2.7
11.6±2.3≠

WNK1 (ODU/mm2)
3.6±0.4
1.0±0.4*
1.5±0.3
0.7±0.2*
4.4±0.5
4.4±0.4τ
3.7±0.5
3.8±0.6≠

p<0.05 vs. respective NS group;
p<0.05 vs. DSS HS group;
p<0.05 vs. SD sc saline HS group.