Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway

Gender is known to be associated with longevity and estrogen administration induced longevity-associated gene expressions is one of the potential mechanisms underlying the benefits of estrogen on life span, whereas the role of testosterone in the regulation of longevity-associated gene expressions remains largely unclear. The klotho gene, predominantly expressed in the kidney, has recently been discovered to be an aging suppressor gene. Here, we investigated the regulatory effects of testosterone on renal klotho gene expression in vivo and in vitro. In testosterone-administered mouse kidney and NRK-52E cells, increased klotho expression was accompanied by the upregulation of the nuclear androgen receptor (AR). Overexpression of AR enhanced the expressions of the klotho mRNA and protein. Conversely, testosterone-induced klotho expression was attenuated in the presence of flutamide, an AR antagonist. A reporter assay and a chromatin immunoprecipitation assay demonstrated that AR directly binds to the klotho promoter via androgen response elements (AREs) which is reconfirmed its importance for AR binding via the element mutation.In summary, our study demonstrated that testosterone upregulates anti-aging klotho together with AR expression in the kidney in vivo and in vitro by recruiting AR onto the AREs of the klotho promoter.
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Gene Source Type: research