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Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease: Nonhemodynamic Renal Protection

Chen Yu^*,, Rujun Gong^*, Abdlla Rifai, Evelyn M. Tolbert^* and Lance D. Dworkin^*

^* Division of Renal Disease, Department of Medicine, and Department of Pathology, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island; and Department of Nephrology, Zhongshan Hospital, School of Medicine, Fudan University, Shanghai, China

Address correspondence to: Dr. Lance D. Dworkin, Division of Renal Disease, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. Phone: 401-444-6843; Fax: 401-444-6849; E-mail: ldworkin{at}lifespan.org

Received for publication July 21, 2006. Accepted for publication January 2, 2007.

Recent evidence suggests that higher-than-usual antihypertensive dosages of renin-angiotensin-aldosterone system blockers may provide additional protection from progression of chronic renal disease; however, there have been few long-term studies, and the underlying mechanisms remain uncertain. This study examined the effects of long-term (14 mo) administration of ultrahigh dosages of the angiotensin receptor blocker candesartan on the progression of renal injury in spontaneously hypertensive rats (SHR). Beginning 8 wk after birth, SHR underwent unilateral nephrectomy and were given vehicle (control), or candesartan at a standard 5 mg/kg per d (T5), high 25 mg/kg per d (T25), or ultrahigh 75 mg/kg per d dosage (T75). After 2 wk, BP was reduced in all treated groups; however, it was better controlled in the high-dosage groups (T25 and T75). Urinary protein was significantly reduced in T75 after 2 wk of treatment and was also declined in the other two treatment groups but only after 2 mo. Exogenous angiotensin II test showed that complete angiotensin receptor blockade was achieved only in the high-dosage groups. Renal inflammation and macrophage (ED-1) infiltration were significantly ameliorated in both T25 and T75 but not in T5 rats. This was associated with the changes of tubular expression of monocyte chemoattractant protein-1, RANTES (regulated upon expression normal T cell expressed and secreted), and the phosphorylated NF-B, a marker for activation. Suppression of ED-1, monocyte chemoattractant protein-1, and RANTES expression and NF-B activation were greater in T75 as compared with T25. These findings suggest that candesartan has dosage-dependent, anti-inflammatory effects that are mediated by suppression of NF-B activation and chemokine expression. Renal protection with high-dosage therapy may depend on these nonhemodynamic effects.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673