Involvement of a-klotho in growth hormone (GH) signaling

Growth hormone (GH) exerts multiple effects on different organs directly or via its main mediator, insulin-like growth factorl (IGF1). In this study, we focused on the novel relationship between GH action and the antiaging hormone a-klotho. Immunofluorescent staining of a-klotho was observed in the renal distal tubules and pituitary glands of somatostatin-and GH-positive cells in wild-type (WT) mice. Treatment of 4-week-old WT mice with GH increased IGF 1 mRNA expression in the pituitary gland, liver, heart, kidney, and bone but increased a-klotho mRNA expression only in the pituitary gland, kidney, and bone. Increased a-klotho protein levels were observed in the kidney but not in the pituitary gland. No induction of a-klotho RNA expression by GH was observed in juvenile mice with kidney disease, indicating GH resistance. Furthermore, GH and a-klotho supplementation in HEK293 cells transfected with GHR increased Janus kinase 2 mRNA (a GH downstream signal) expression compared to supplementation with GH alone. In conclusion, we suggest that 1) the kidney is the main source of secreted a-klotho, which is detected in blood by the downstream action of GH, 2) a-klotho induction by GH is resistant in kidney disease, and 3) a-klotho might be an enhanced regulator of GH signaling.