Abstract 384: Tumor Necrosis Factor-alpha Antagonism Attenuates Hypertension and Renal Injury Induced by Chronic Blockade of Nitric Oxide and High Salt Intake in Mice
Earlier, we demonstrated that systemic blockade of nitric oxide (NO) generation by acute infusion of nitro-L-arginine methyl ester (L-NAME) in mice increases plasma and renal levels of tumor necrosis factor-alpha (TNF-α). In the present study, we examined the role of TNF-α in mediating hypertension and renal injury responses to chronic NO blockade by evaluating the responses to chronic administration of L-NAME (0.05 μg/g/min; by osmotic mini-pump) for 3 wks in mice (C57BL6) treated with or without TNF-α receptor antagonist, etanercept (ETN; 5 mg, ip, every alternate day). These mice were given either normal (NS; 0.03% NaCl) or high salt (HS; 4% NaCl) containing diets. Systemic blood pressure (BP) was measured by tail-cuff plethysmography. At the end of the experimental period, mice were sacrificed to collect plasma and renal tissue samples to measure TNF-α level by ELISA and to determine the extent of tissue injury such as glomerulosclerosis (GS; PAS staining) and renal interstitial fibrosis (RIF; Trichrome staining). L-NAME treatment caused increase in BP which was greater in HS (104±3 to 139±3 mmHg; n=6) than in NS group (96±6 to 124±6 mmHg; n=6). ETN treatment significantly attenuated this increase in BP in both L-NAME+HS (119±11 mmHg; n=6) and in L-NAME+NS (115±8 mmHg, n=6) groups. Renal tissue level of TNF-α was higher in L-NAME+NS (664±100 vs 325±73 pg/mg protein) and in L-NAME+HS (391±38 vs 114±17 pg/mg protein) groups compared to the levels in groups given NS (n=5) or HS (n=5) diet alone. However, the changes in plasma level of TNF-α due to chronic L-NAME treatment were minimal. ETN treatment lowered renal TNF-α level in L-NAME+NS (356±60 pg/mg protein) and in L-NAME+HS (259±65 pg/mg protein) groups. L-NAME treatment significantly increased GS (7.1±1.0 vs 17.9±2.3 % sclerosis area) and RIF, (1.5±0.1 vs 5.8±0.6 % fibrotic area) in HS group. However, these changes were minimal in NS group (GS, 10.3±1.0 vs 13.2±1.5 % and RIF, 1.3±0.1 vs 2.4±0.3 %). ETN treatment markedly attenuated the GS (11.8±0.4% and 11.9±0.6 %) and RIF (2.6±0.3% and 1.9±0.3%) both in L-NAME+HS and in L-NAME+NS groups. These data demonstrate that an enhancement in TNF-α activity is involved in mediating hypertension and renal injury responses to chronic NO blockade and HS intake.
- © 2013 by American Heart Association, Inc.