Combination Therapy with Olmesartan and Temocapril Ameliorates Renal Damage and Upregulates the klotho Gene in 5/6 Nephrectomized Spontaneously Hypertensive Rats

Recent studies suggest that chronic kidney disease may induce cardiovascular disease through oxidative stress, and that the aging suppressor gene klotho reduces oxidative stress in the kidney. In this study, we examined the changes in klotho gene expression, and the renoprotective effects of olmesartan (OLM), angiotensin II receptor blocker (ARB) alone or in combination with temocapril (TEM), angiotensin-converting enzyme inhibitor (ACEI) in 5/6-nephrectomized (5/6-Nx) spontaneously hypertensive rats. Male 5/6-Nx spontaneously hypertensive rats were randomly assigned to 5 groups as follows: control group; 5/6-Nx group, 5/6-Nx rats; low OLM group, 5/6-Nx rats administered low-dose OLM (3 mg/kg/day); high OLM group, 5/6-Nx rats administered high-dose OLM (10 mg/kg/day); OLM+TEM group, 5/6-Nx rats administered high-dose OLM and TEM (10 mg/kg/day each). These drugs were administered for 12 weeks. Systolic blood pressure, glomerular sclerosis and transforming growth factor beta 1 mRNA in high OLM and OLM+TEM groups were significantly lower than that in the 5/6-Nx group. Only the OLM+TEM group showed improvement of serum creatinine and urinary 8-hydroxy-2'-deoxyguanosine. Ex-pression of klotho mRNA, which was downregulated in the 5/6-Nx group, was upregulated in the high OLM and OLM+TEM groups. OLM dose-dependently prevented klotho mRNA downregulation in 5/6-Nx rats, thus confirming a renoprotective effect. In addition, combination therapy of OLM and TEM was more effective than OLM alone. In conclusion, the combination of OLM and TEM inhibits the progression of renal damage in 5/6-Nx rats through the upregulation of klotho gene.