Renal NF-kappaB activation and TNF-alpha upregulation correlate with salt-sensitive hypertension in Dahl salt-sensitive rats.
Molecular mechanisms of salt-sensitive (SS) hypertension related to renal inflammation have not been defined. We seek to determine whether a high-salt (HS) diet induces renal activation of NF-kappaB and upregulation of TNF-alpha related to the development of hypertension in Dahl SS rats. Six 8-wk-old male Dahl SS rats received a HS diet (4%), and six Dahl SS rats received a low-sodium diet (LS, 0.3%) for 5 wk. In the end, mean arterial pressure was determined in conscious rats by continuous monitoring through a catheter placed in the carotid artery. Mean arterial pressure was significantly higher in the HS than the LS group (177.9 +/- 3.7 vs. 109.4 +/- 2.9 mmHg, P < 0.001). There was a significant increase in urinary albumin secretion in the HS group compared with the LS group (22.3 +/- 2.6 vs. 6.1 +/- 0.7 mg/day; P < 0.001). Electrophoretic mobility shift assay demonstrated that the binding activity of NF-kappaB p65 proteins in the kidneys of Dahl SS rats was significantly increased by 53% in the HS group compared with the LS group (P = 0.007). ELISA indicated that renal protein levels of TNF-alpha, but not IL-6, interferon-gamma, and CCL28, were significantly higher in the HS than the LS group (2.3 +/- 0.8 vs. 0.7 +/- 0.2 pg/mg; P = 0.036). We demonstrated that plasma levels of TNF-alpha were significantly increased by fivefold in Dahl SS rats on a HS diet compared with a LS diet. Also, we found that increased physiologically relevant sodium concentration (10 mmol/l) directly stimulated NF-kappaB activation in cultured human renal proximal tubular epithelial cells. These findings support the hypothesis that activation of NF-kappaB and upregulation of TNF-alpha are the important renal mechanisms linking proinflammatory response to SS hypertension.
Gu
Jian-Wei
JW
Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA. jgu@physiology.umsmed.edu
Tian
Niu
N
Shparago
Megan
M
Tan
Wei
W
Bailey
Amelia P
AP
Manning
R Davis
RD
D000818:Animals; D006977:Hypertension, Renal / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009393:Nephritis / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary; D013223:Statistics as Topic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
D016328:NF-kappa B; D017673:Sodium Chloride, Dietary; D014409:Tumor Necrosis Factor-alpha