Long-term, high-dosage candesartan suppresses inflammation and injury in chronic kidney disease: nonhemodynamic renal protection.
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.
Yu
Chen
C
Division of Renal Disease, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.
Gong
Rujun
R
Rifai
Abdlla
A
Tolbert
Evelyn M
EM
Dworkin
Lance D
LD
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000187:drug effects / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy*; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000008:administration & dosage*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D016328:NF-kappa B; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C081643:candesartan