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-kappaB, a marker for activation. Suppression of ED-1, monocyte chemoattractant protein-1, and RANTES expression and NF-kappaB 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-kappaB activation and chemokine expression. Renal protection with high-dosage therapy may depend on these nonhemodynamic effects.