Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases

The human aging process is associated with vascular endothelial dysfunction . However, humoral factors which might protect against endothelial dysfunct ion during aging have not yet been identified. We recently identified the k lotho gene as a possible regulator of human aging. In the present study usi ng the klotho-deficient heterozygous mouse, we examined whether the Klotho protein is a humoral factor protecting against endothelial dysfunction. We further clotted rat klotho cDNA and investigated whether klotho mRNA expres sion in rat kidney is altered under pathological conditions such as hyperte nsion, hyperlipidemia, renal failure, and inflammatory stress. The Klotho p rotein itself, or its metabolites, promotes endothelial NO production in ao rta as well as arterioles, and klotho mRNA in kidney is downregulated under sustained circulatory stress.