Published Online
on January 16, 2006

A more recent version of this article appeared on March 1, 2006

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Submitted on September 30, 2005
Revised on October 26, 2005

Tumor Necrosis Factor Blockade Increases Renal Cyp2c23 Expression and Slows the Progression of Renal Damage in Salt-Sensitive Hypertension

Ahmed A. Elmarakby; Jeffrey E. Quigley; David M. Pollock; and John D. Imig^*

From the Departments of Physiology (A.A.E., J.E.Q., D.M.P.) and Surgery (D.M.P., J.D.I.) and Vascular Biology Center (D.M.P., J.D.I.), Medical College of Georgia, Augusta.

^* To whom correspondence should be addressed. E-mail: jdimig{at}mail.mcg.edu.

Abstract--We hypothesized that the downregulation of Cyp2c by tumor necrosis factor (TNF) 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- 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- contributes to downregulation of Cyp2c23, blood pressure regulation, and renal injury in angiotensin high-salt hypertension.

Key words: sodium, dietary • angiotensin • tumor necrosis factor • blood pressure • proteinuria • metabolism

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