Tian N, Gu JW, Jordan S, Rose RA, Hughson MD, Manning RD Jr. Immune suppression prevents renal damage and dysfunction and reduces arterial pressure in salt-sensitive hypertension. Am J Physiol Heart Circ Physiol 292: H1018 -H1025, 2007. First published October 13, 2006; doi:10.1152/ajpheart.00487.2006.-The goal of this study was to test the hypothesis that renal infiltration of immune cells in Dahl S rats on increased dietary sodium intake contributes to the progression of renal damage, decreases in renal hemodynamics, and development of hypertension. We specifically studied whether anti-immune therapy, using mycophenolate mofetil (MMF), could help prevent increases in renal NF-B activation, renal infiltration of monocytes/macrophages, renal damage, decreases in glomerular filtration rate (GFR) and renal plasma flow, and increases in arterial pressure. Seventy-four 7-to 8-wk-old Dahl S, Rapp strain rats were maintained on an 8% Na, 8% Na ϩ MMF (20 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), 0.3% Na, or 0.3% Na ϩ MMF diet for 5 wk. Arterial and venous catheters were implanted at day 21. By day 35, renal NF-B in 8% Na rats was 47% higher than in 0.3% Na rats and renal NF-B was 41% lower in 8% Na ϩ MMF rats compared with the 8% Na group. MMF treatment significantly decreased renal monocyte/macrophage infiltration and renal damage and increased GFR and renal plasma flow. In high-NA Dahl S rats mean arterial pressure increased to 182 Ϯ 5 mmHg, and MMF reduced this arterial pressure to 124 Ϯ 3 mmHg. In summary, in Dahl S rats on high sodium intake, treatment with MMF decreases renal NF-B and renal monocyte/macrophage infiltration and improves renal function, lessens renal injury, and decreases arterial pressure. This suggests that renal infiltration of immune cells is associated with increased arterial pressure and renal damage and decreasing GFR and renal plasma flow in Dahl salt-sensitive hypertension. renal failure; macrophages; renal hemodynamics; nuclear factor-B SEVERAL MECHANISMS have been found to contribute to the etiology of salt-sensitive hypertension, including reduced levels of NO (7) and elevated oxidative stress (12,29). In addition to these factors, there is emerging evidence indicating that the immune system may play an important role in salt-sensitive hypertension.In several models of hypertension, renal tubulointerstitial infiltration of macrophages and lymphocytes occurs. Renal immunocompetent cells have been found in DOCA hypertension (27), post-angiotensin II (ANG) salt-sensitive hypertension (21), hypertension following NO inhibition (20), protein overload nephropathy (1), the spontaneously hypertensive rate (SHR) (22) and the double-transgenic rat (dTGR) that has human renin and angiotensinogen genes (18). Anti-immune therapy administered to each of the above models of hypertension successfully decreased arterial pressure (24).Dahl salt-sensitive hypertension is characterized by increases in oxidative stress, severe renal damage, and decreases in renal hemodynamics (29); however, the role of renal immune cell infil...

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...

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