title: Tumor necrosis factor alpha blockade increases renal Cyp2c23 expression and slows the progression of renal damage in salt-sensitive hypertension.
abstract: We hypothesized that the downregulation of Cyp2c by tumor necrosis factor (TNF) alpha contributes to hypertension and renal injury in salt-sensitive angiotensin hypertension. Male Sprague-Dawley rats were fed a high-salt diet (8% NaCl), and osmotic minipumps were implanted to deliver angiotensin II for 14 days. Rats were divided into 3 groups: high salt, angiotensin high salt, and angiotensin high salt administered the TNF-alpha blocker, etanercept. Arterial pressure increased from 94+/-5 to 148+/-7 mm Hg during week 1 in the angiotensin high-salt group, whereas etanercept slowed blood pressure elevation during the first week in the treated group (90+/-2 to 109+/-6 mm Hg). After 2 weeks, arterial pressure increased to 156+/-11 mm Hg in the angiotensin high-salt group and 141+/-6 mm Hg in the etanercept-treated group. Albuminuria and proteinuria were significantly elevated in angiotensin high-salt rats and were reduced in the etanercept-treated rats. Urinary monocyte chemoattractant protein-1 excretion significantly increased in the angiotensin high-salt group (275+/-47 versus 81+/-19 ng/day) and was decreased in the etanercept-treated group (153+/-31 ng/day). Angiotensin high-salt rats also had a significant increase in renal monocyte/macrophage infiltration, and this was again attenuated by etanercept treatment. Renal expression of Cyp2c23 decreased, whereas renal epoxide hydrolase expression increased in angiotensin high-salt rats. Etanercept treatment increased Cyp2c23 expression and lowered epoxide hydrolase expression. These data suggest that TNF-alpha contributes to downregulation of Cyp2c23, blood pressure regulation, and renal injury in angiotensin high-salt hypertension.
authors.affiliation: Department of Physiology, 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: David M
authors.initials: DM
authors.lastname: Pollock
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
mesh_terms: D000419:Albuminuria / Q000503:physiopathology; D000809:Angiotensins; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018450:Disease Progression; D000068800:Etanercept; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D007074:Immunoglobulin G / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D011507:Proteinuria / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000809:Angiotensins; C000717351:Cyp2c23 protein, rat; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D017673:Sodium Chloride, Dietary; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D000068800:Etanercept