AMP‐dependent kinase stimulates the expression of αKlotho

Abstract

Renal αKlotho along with fibroblast growth factor 23 regulates phosphate and vitamin D metabolism. Its cleavage yields soluble Klotho controlling intracellular processes. αKlotho has anti‐inflammatory and antioxidant effects and is nephro‐ and cardioprotective. AMP‐dependent kinase (AMPK) is a nephro‐ and cardioprotective energy sensor. Given that both αKlotho and AMPK have beneficial effects in similar organs, we studied whether AMPK regulates αKlotho gene expression in Madin–Darby canine kidney, normal rat kidney 52E, and human kidney 2 cells. Using quantitative real‐time PCR and western blotting, we measured αKlotho expression upon pharmacological manipulation or siRNA‐mediated knockdown of AMPKα. AMPK activator 5‐aminoimidazole‐4‐carboxamide ribonucleoside (AICAR) enhanced αKlotho expression, an effect reduced in the presence of AMPK inhibitor compound C or siRNA targeting AMPK catalytic α‐subunits (α1 and α2). Similarly, AMPK activators metformin and phenformin upregulated αKlotho transcripts. Taken together, our results suggest that AMPK is a powerful inducer of αKlotho and could thereby contribute to the development of future therapeutic interventions.