Chronic renal failure (CRF) markedly accelerates the development of atherosclerosis, but the pathogenesis of uremic atherosclerosis remains to be elucidated. The klotho gene, predominantly expressed in the kidney, plays a key role in regulating aging and the development of age-related diseases in mammals. A loss of klotho results in multiple aging-like phenotypes including atherosclerosis. This study examines the relationship between the klotho expression and the development of accelerated atherosclerosis in uremic state. Eight-week-old apolipoprotein E-deficient (apo-E(-/-)) male mice underwent 5/6 partial kidney ablation to induce CRF or sham-operation. At 6 wk after nephrectomy, CRF mice showed significantly increased aortic plaque area fraction, aortic root plaque area and aortic cholesterol content as compared with non-CRF mice. Serum urea, total cholesterol and triglyceride concentrations were significantly higher in CRF apo-E(-/-) mice compared with non-CRF controls. Moreover, the expression of renal klotho gene and the serum levels of klotho protein were markedly decreased in CRF mice compared with controls. These results suggested that CRF favored atherosclerosis in apo-E(-/-) mice and uremic atherosclerosis was accompanied by down-regulation of klotho expression.
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