Klotho response to treatment with growth hormone and the role of IGF-I as a mediator

Context Klotho is an aging-modulating protein expressed mainly in the kidneys, which can be cleaved and shed to act as a circulating hormone. Several lines of evidence suggest a tight interaction between klotho and the GH–IGF-I axis. We showed previously that klotho levels are decreased in pediatric patients with growth hormone deficiency (GHD). Our aim now is to investigate the effect of GH therapy on klotho levels in these patients and to elucidate the role of IGF-1 in mediating secretion of klotho. Basic Procedures Klotho levels were measured in 29 GHD pediatric patients (males = 15, aged 12.2 ± 3.3 years), treated with GH for 2.5 ± 2.8 years; nineteen patients had samples obtained both before and during treatment. The effect of IGF-I and its downstream effectors on secretion of klotho to media was studied in COS-7 cells overexpressing klotho. Main Findings Klotho levels increased under GH treatment (from 1321 ± 691 pg/ml to 3380 ± 2120 pg/ml, p < 0.001), and were higher compared to controls (1645 ± 778 pg/ml, p < 0.001), resulting in supraphysiological levels. Fold-increase in klotho correlated with fold-increase in IGF-I (r = 0.63, p = 0.004). Studies in COS-7 cells overexpressing klotho revealed mTOR-dependent induction of klotho shedding by IGF-I. Principal Conclusions Klotho levels increased during GH treatment of pediatric GHD patients. This increase was associated with an increase in IGF-I levels. Furthermore, we showed, for the first time, a direct role of IGF-I in the regulation of klotho's shedding which depends on activation of the AKT-mTOR pathway. Our findings add further support for the close association between klotho and the GH/IGF-I axis.