The Effects of Olmesartan and Alfacalcidol on Renoprotection andklotho Gene Expression in 5/6 Nephrectomized Spontaneously HypertensiveRats

摘要

Recently, an angiotensin inhibitor has been shown to upregulate the klotho mRNA level in chronic renal failure. In addition, the administration of vitamin D has been reported to improve the mortality of patients with chronic renal failure. In this study, we examined the effects of an angiotensin inhibitor and/or vitamin D on the progression of chronic renal failure by using male 5/6 nephrectomized (5/6Nx) spontaneously hypertensive rats. Male 5/6Nx spontaneously hypertensive rats were assigned to 4 groups as follows: 5/6Nx group, 5/6Nx rats; Alf group, 5/6Nx rats administered alfacalcidol (0.2 μg/kg/day); Olm group, 5/6Nx rats administered olmesartan (15 mg/kg/day); Alf + Olm group, 5/6Nx rats administered alfacalcidol (0.2 μg/kg/day) and olmesartan (15 mg/kg/day). These drugs were administered for 12 weeks. Systolic blood pressure in the Alf, Olm and Alf + Olm groups were significantly decreased relative to that in the 5/6Nx group during the 12-week experimental period. As a result, all treated groups showed renoprotection based on improvement of the systolic blood pressure, urinary protein excretion and histological renal fibrosis. Combination therapy of alfacalcidol and olmesartan was more effective than either alfacalcidol or olmesartan alone. Expression of klotho mRNA was significantly upregulated in the Alf + Olm group in comparison with in the 5/6Nx group.Serum levels of fibroblast growth factor 23 in the Alf group and the Alf + Olm group weresignificantly higher than those in the 5/6Nx group and the Olm group. In conclusion, thecombination of Olm and Alf inhibited the progression of renal damage in the 5/6Nx groupthrough the strong antihypertensive effect as well as the upregulation of theklotho gene.