J Korean Med Sci.  1999 Dec;14(6):653-658. 10.3346/jkms.1999.14.6.653.

Individual or combined effects of enalapril and verapamil on chronic cyclosporine nephrotoxicity in rats

• Lee SK
• Park JY
• Yu ES
• Yang WS
• Kim SB
• Park SK
• Park JS

• KMID: 646042
• DOI: http://doi.org/10.3346/jkms.1999.14.6.653

Abstract

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.

Keyword

Cyclosporine; Enalapril; Gene expression; Verapamil

MeSH Terms

Angiotensin-Converting Enzyme Inhibitors/therapeutic use*
Animal
Calcium Channel Blockers/therapeutic use*
Cyclosporine/adverse effects
Drug Therapy, Combination
Enalapril/therapeutic use*
Enalapril/administration & dosage
Endothelin-1/metabolism
Endothelin-1/genetics
Gene Expression Regulation/drug effects
Immunosuppressive Agents/adverse effects
Kidney Cortex/metabolism
Male
Nephritis/drug therapy*
Nephritis/chemically induced
Procollagen/metabolism
Procollagen/genetics
RNA, Messenger/analysis
Rats
Rats, Wistar
Sialoglycoproteins/metabolism
Sialoglycoproteins/genetics
Transforming Growth Factor beta/metabolism
Transforming Growth Factor beta/genetics
Verapamil/therapeutic use*
Verapamil/administration & dosage