Tian N, Moore RS, Braddy S, Rose RA, Gu JW, Hughson MD, Manning RD Jr. Interactions between oxidative stress and inflammation in salt-sensitive hypertension. Am J Physiol Heart Circ Physiol 293: H3388-H3395, 2007. First published October 5, 2007; doi:10.1152/ajpheart.00981.2007.-The goal of this study was to test the hypothesis that increases in oxidative stress in Dahl S rats on a high-salt diet help to stimulate renal nuclear factor-B (NF-B), renal proinflammatory cytokines, and chemokines, thus contributing to hypertension, renal damage, and dysfunction. We specifically studied whether antioxidant treatment of Dahl S rats on high Na intake would decrease renal inflammation and thus attenuate the hypertensive and adverse renal responses. Sixty-four 7-to 8-wk-old Dahl S or R/Rapp strain rats were maintained for 5 wk on high Na (8%) or high Na ϩ vitamins C (1 g/l in drinking water) and E (5,000 IU/kg in food). Arterial and venous catheters were implanted at day 21. By day 35 in the high-Na S rats, antioxidant treatment significantly increased the renal reduced-to-oxidized glutathione ratio and decreased renal cortical H 2O2 and O2•Ϫ release and renal NF-B. Antioxidant treatment with vitamins C and E in high-Na S rats also decreased renal monocytes/macrophages in the glomeruli, cortex, and medulla, decreased tumor necrosis factor-␣ by 39%, and decreased monocyte chemoattractant protein-1 by 38%. Vitamin-treated, high-Na S rats also experienced decreases in arterial pressure, urinary protein excretion, renal tubulointerstitial damage, and glomerular necrosis and increases in glomerular filtration rate and renal plasma flow. In conclusion, antioxidant treatment of high-Na Dahl S rats decreased renal inflammatory cytokines and chemokines, renal immune cells, NF-B, and arterial pressure and improved renal function and damage. renal failure; cytokines; chemokines; renal hemodynamics; salt-sensitivity; nuclear factor-B STUDIES IN HUMAN AND EXPERIMENTAL HYPERTENSION have shown that increases in oxidative stress may play an important role in the etiology and maintenance of increased blood pressure. Increased oxidative stress has been found in the spontaneously hypertensive rat (SHR), the stroke-prone SHR, DOCA-salt hypertensive rats, and the Dahl salt-sensitive (S) rat (5,6,10,21,22,41,49). In addition, evidence for increased renal oxidative stress has been found in lead-induced hypertension (48), coarctation of the aorta (3), and in the Dahl S rat (22, 43).There is considerable evidence for the involvement of the immune system in hypertension. Studies in several models of experimental hypertension have found renal invasion of lymphocytes and macrophages (24,29,31,40,45). Anti-immune therapy administered to these models of hypertension successfully decreased arterial pressure (32) and renal levels of immunocompetent cells.Our laboratory has shown that the Dahl S rat, when challenged with a high-salt diet, experiences both oxidative stress and inflammation (45), and this is associated with hypertension and considerable r...

The goal of this study was to test the hypothesis that NADPH oxidase contributes importantly to renal cortical oxidative stress and inflammation, as well as renal damage and dysfunction, and increases in arterial pressure. Fifty-four 7- to 8-wk-old Dahl salt-sensitive (S) or R/Rapp strain rats were maintained for 5 wk on a high sodium (8%) or high sodium + apocynin (1.5 mmol/l in drinking water). Arterial and venous catheters were implanted on day 21. By day 35 in the high-Na S rats, mRNA expression of renal cortical gp91phox, p22phox, p47phox, and p67phox NADPH subunits in S rats increased markedly, and treatment of high-Na S rats with the NADPH oxidase inhibitor apocynin resulted in significant decreases in mRNA expression of these NADPH oxidase subunits. At the same time, in apocynin-treated S rats 1) renal cortical GSH/GSSG ratio increased, 2) renal cortical O2(.-) release and NADPH oxidase activity decreased, and 3) renal glomerular and interstitial damage markedly fell. Apocynin also decreased renal cortical monocyte/macrophage infiltration, and apocynin, but not the xanthine oxidase inhibitor allopurinol, attenuated decreases in renal hemodynamics and lowered arterial pressure. These data suggest that NADPH oxidase plays an important role in causing renal cortical oxidative stress and inflammation, which lead to decreases in renal hemodynamics, renal cortical damage, and increases in arterial pressure.

The goal of this study was to determine if renal oxidative stress increases renal inflammation in Dahl salt‐sensitive hypertension. Dahl salt‐sensitive (S) and salt‐resistant (R) rats were equipped with arterial and venous catheters and subjected to a 5‐week diet of high Na (8% NaCl) or high Na + Vitamins C and E. Mean arterial pressure (MAP) was measured continuously throughout the last 10 days. By the end of week 5, renal cortical O2·− release in S rats was significantly reduced in the S rats with vitamins (1204±100 vs 821±63 RLU/min/mg). At the same time, renal inflammation in the S rats with high Na vitamin treatment group also significantly decreased compared to S high Na group (TNFα, 0.96±0.1 vs 0.59±0.1 pg/mg; MCP‐1, 16±1 vs 10±1 pg/mg; monocyte/macrophage infiltration, 15±2 vs 3±1 cells/mm2), but IL‐6 was unchanged (4±1 vs 4±0 pg/mg). Interestingly, in the R rat, vitamin treatment decreased renal macrophage infiltration and MCP‐1 without a change in MAP. Vitamin treatment in S high Na rats decreased MAP and urinary protein excretion and increased GFR and renal plasma flow. In summary, vitamin C/E treatment in Dahl S rats on high Na intake decreased renal oxidative stress and renal markers of inflammation and improved renal damage and dysfunction. In conclusion, renal oxidative stress is associated with increased renal inflammation in Dahl salt‐sensitive hypertension. Support: NIH Grant HL51971.