Klotho is a transmembrane protein, protease and hormone, which is expressed in several tissues with highest expression in the kidney. Overexpression of klotho delays the appearance of age-related disorders and substantially increases the life span. Conversely, klotho-deficiency results in excessive formation of 1,25(OH)₂D₃, growth deficit, accelerated aging and early death. Several age-related disorders are fostered by glucocorticoids. The present study thus explored whether klotho expression in human embryonic kidney (HEK293) cells is influenced by the glucocorticoid dexamethasone. Klotho transcript levels and protein abundance were determined by RT-PCR and Western blotting, respectively. As a result, exposure of serum deprived HEK293 cells to dexamethasone was followed by a significant decline of klotho transcript levels and protein abundance. The effect was paralleled by an upregulation of the mRNA encoding the serum and glucocorticoid inducible kinase SGK1. Thus, further experiments explored the involvement of SGK1 in the dexamethasone sensitive klotho regulation. Overexpression of constitutive active ^S422DSGK1, but not of the inactive ^K127NSGK1 was followed by significant decrease of klotho transcript levels. Administration of the SGK1 inhibitor GSK650394 significantly enhanced klotho expression and abrogated the downregulation of klotho transcript levels following dexamethasone exposure. In conclusion, the glucocorticoid dexamethasone downregulates klotho expression, an effect at least partially due to upregulation of SGK1 transcription.