Individual or combined effects of enalapril and verapamil on chronic cyclosporine nephrotoxicity in rats.
Previous studies have demonstrated that enalapril and verapamil seem to attenuate the cyclosporine nephrotoxicity. However, the mechanisms have not been completely understood, especially on molecular events. The aim of this study was to examine the effect of individual or combined treatment on osteopontin, TGF-beta, endothelin-1 and procollagen alpha 1(I) mRNA expressions. Enalapril (50 mg/L in drinking water) and verapamil (0.5 mg/kg/day, subcutaneously), alone or in combination, were administered to rats with chronic cyclosporine nephrotoxicity (cyclosporine, 25 mg/kg/day, subcutaneously) (n = 5 each). Five rats treated with olive oil vehicle were used as control. After 4 weeks, biochemical parameters were measured, and renal cortical mRNA levels were evaluated by Northern blot analysis. Cyclosporine reduced renal creatinine clearance significantly and induced renal cortical osteopontin, TGF-beta, endothelin-1 and procollagen alpha 1(I) gene expressions around 13.5 +/- 1.3, 2.4 +/- 0.2, 1.5 +/- 0.1, 1.9 +/- 0.1 folds, respectively. Individual treatment with enalapril or verapamil significantly suppressed the osteopontin and TGF-beta mRNA expression, but not endothelin-1 and procollagen alpha 1(I). Combined treatment also inhibited the osteopontin and TGF-beta mRNA expression but there was no difference between combined and individual treatment. In conclusion, enalapril or verapamil significantly blunted the cyclosporine-induced osteopontin and TGF-beta gene expressions. However, combined treatment did not show any additive effect.
Lee
S K
SK
Department of Internal Medicine, University of Ulsan, Seoul, Korea.
Park
J Y
JY
Yu
E S
ES
Yang
W S
WS
Kim
S B
SB
Park
S K
SK
Park
J S
JS
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D016572:Cyclosporine / Q000009:adverse effects; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000008:administration & dosage / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D009393:Nephritis / Q000139:chemically induced / Q000188:drug therapy*; D053495:Osteopontin; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014700:Verapamil / Q000008:administration & dosage / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D019332:Endothelin-1; D007166:Immunosuppressive Agents; D011347:Procollagen; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D016212:Transforming Growth Factor beta; D053495:Osteopontin; D004656:Enalapril; D016572:Cyclosporine; D014700:Verapamil