NFkB Mediates Renal Sodium Retention via the Sodium Chloride Cotransporter in Zinc Deficiency‐Induced Hypertension

Abstract

Background : Zinc deficiency (ZnD) is comorbid with diseases such as kidney disease and diabetes. Individuals in these populations have a higher prevalence of hypertension. Recently, we reported that ZnD promotes hypertension in mice. The blood pressure elevations were accompanied with increased Na+ retention via the renal Sodium Chloride Cotransporter (NCC). Although our published results indicate that zinc plays a critical role in blood pressure and NCC regulation, the mechanisms involved were not investigated. Hypothesis : Since nuclear factor-kB (NFkB) mediates ZnD-induced detrimental effects, we tested the hypothesis that NFκB drives ZnD-induced NCC upregulation and subsequently Na+ retention and hypertension. Experimental Design : To determine the role of NFκB in ZnD-induced renal Na+ retention and hypertension, adult male C57Bl/6 mice were fed a ZnD diet (5 weeks) followed by administration of the NFκB inhibitor - caffeic acid phenethyl ester (CAPE; 1 week). Systolic blood pressure and urinary Na+ concentrations were examined. To examine if NFkB mediates ZnD-induced NCC upregulation, mouse distal convoluted tubule (mDCT) cells were treated with the zinc chelator N, N, N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) ± CAPE, a NFκB inhibitor. After 24 hours, NCC mRNA and protein expressions, as well as activation, were assessed by qRT-PCR, Western blot and immunofluorescence, respectively. Results : In mice, ZnD promoted hypertension and renal Na+ retention. Further, increased NCC expression was accompanied with enhanced NFkB expression in ZnD mice. However, CAPE administration lowered blood pressure and elevated urinary Na+ concentrations. In mDCT cells, TPEN-induced NCC upregulation was prevented by CAPE treatment. Conclusions : Together, these results demonstrate that 1) NFkB is a novel NCC regulator and 2) NFkB mediates ZnD-induced renal Na+ retention and hypertension. These novel findings indicate that ZnD drives renal NFkB activation thereby stimulating NCC-mediated Na+ retention and promoting hypertension. Significance : This study identifies NFkB as a possible pharmacological target to mitigate hypertension.