title: TNF-alpha inhibition reduces renal injury in DOCA-salt hypertensive rats.
abstract: Studies suggest that the inflammatory cytokine TNF-alpha plays a role in the prognosis of end-stage renal diseases. We previously showed that TNF-alpha inhibition slowed the progression of hypertension and renal damage in angiotensin II salt-sensitive hypertension. Thus, we hypothesize that TNF-alpha contributes to renal inflammation in a model of mineralocorticoid-induced hypertension. Four groups of rats (n = 5 or 6) were studied for 3 wk with the following treatments: 1) placebo, 2) placebo + TNF-alpha inhibitor etanercept (1.25 mg.kg(-1).day(-1) sc), 3) deoxycorticosterone acetate + 0.9% NaCl to drink (DOCA-salt), or 4) DOCA-salt + etanercept. Mean arterial blood pressure (MAP) measured by telemetry increased in DOCA-salt rats compared with baseline (177 +/- 4 vs. 107 +/- 3 mmHg; P < 0.05), and TNF-alpha inhibition had no effect in the elevation of MAP in these rats (177 +/- 8 mmHg). Urinary protein excretion significantly increased in DOCA-salt rats compared with placebo (703 +/- 76 vs. 198 +/- 5 mg/day); etanercept lowered the proteinuria (514 +/- 64 mg/day; P < 0.05 vs. DOCA-salt alone). Urinary albumin excretion followed a similar pattern in each group. Urinary monocyte chemoattractant protein (MCP)-1 and endothelin (ET)-1 excretion were also increased in DOCA-salt rats compared with placebo (MCP-1: 939 +/- 104 vs. 43 +/- 7 ng/day, ET-1: 3.30 +/- 0.29 vs. 1.07 +/- 0.03 fmol/day; both P < 0.05); TNF-alpha inhibition significantly decreased both MCP-1 and ET-1 excretion (409 +/- 138 ng/day and 2.42 +/- 0.22 fmol/day, respectively; both P < 0.05 vs. DOCA-salt alone). Renal cortical NF-kappaB activity also increased in DOCA-salt hypertensive rats, and etanercept treatment significantly reduced this effect. These data support the hypothesis that TNF-alpha contributes to the increase in renal inflammation in DOCA-salt rats.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500, USA.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Elmarakby
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Quigley
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Pollock
authors.forename: David M
authors.initials: DM
authors.lastname: Pollock
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D018932:Chemokine CCL2 / Q000378:metabolism; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D000068800:Etanercept; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D007074:Immunoglobulin G / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008901:Mineralocorticoids; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D019332:Endothelin-1; D007074:Immunoglobulin G; D008901:Mineralocorticoids; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003900:Desoxycorticosterone; D000068800:Etanercept