Augmentation of nitric oxide deficient hypertension by high salt diet is associated with reduced TNF-α receptor type 1 expression in the kidneys.

Abstract

High salt (HS) intake induces an augmented hypertensive response to nitric oxide (NO) inhibition, though it causes minimal changes in blood pressure (BP) in NO intact condition. The cause of such augmentation is not known. HS induces tumor necrosis factor-alpha (TNFα) production that causes natriuresis via activation of its' receptor type 1 (TNFR1). We hypothesized that NO deficiency reduces renal TNFR1 activity, leading to enhanced sodium retention and hypertension. We examined the changes in renal TNFR1 protein expression (Immunohistochemistry analyses) after HS (4% NaCl) intake in wild-type mice (WT, C57BL6) treated with a NO synthase (NOS) inhibitor, nitro-L-arginine methyl ester (L-NAME; 0.05mg/min/g; osmotic mini-pump), as well as in endothelial NOS knockout mice (eNOSKO) and compared the responses in WT mice with normal salt (NS; 0.3% NaCl) intake. BP was measured with tail-cuff plethysmography and 24-hour urine collections were made using metabolic cages. HS alone did not alter mean BP in untreated mice (76±3 to 77±1 mmHg) but induced an augmented response in L-NAME treated (106±1 vs 97±2 mmHg) and in eNOSKO (107±2 vs 89±3 mmHg) mice. The percentage area of TNFR1 expression in renal tissue was higher in WT+HS (4.1+0.5%) than in WT+NS mice (2.7±0.6%). However, TNFR1 expression was significantly lower in L-NAME treated WT+NS (0.9±0.1%) and in eNOSKO+NS (1.4±0.2%) than in both WT+NS and WT+HS mice. These data indicate that TNFR1 activity is downregulated in NO deficient conditions, which facilitates salt retention leading to augmented hypertension during HS intake.