Tami Rubinek1, Shiri Shahmoon2, Ayelet Shabtay-Orbach1, Michal Ben Ami3, Yael Levy-Shraga3, Kineret Mazor-Aronovitch4, Yonatan Yeshayahu3, Ram Doolman5, Rina Hemi6, Hannah Kanety6, Ido Wolf2, Dalit Modan-Moses7. 1. Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 2. Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 3. Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel. 4. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel. 5. lnstitute of Chemical Pathology, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel. 6. Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel. 7. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel. Electronic address: dmodan@sheba.health.gov.il.
Abstract
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±3.3years), treated with GH for 2.5±2.8years; 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±691pg/ml to 3380±2120pg/ml, p<0.001), and were higher compared to controls (1645±778pg/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.
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±3.3years), treated with GH for 2.5±2.8years; 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±691pg/ml to 3380±2120pg/ml, p<0.001), and were higher compared to controls (1645±778pg/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.
Authors: V Guarnotta; G Pizzolanti; R Petrancosta; S Radellini; C Baiamonte; C Giordano Journal: J Endocrinol Invest Date: 2022-03-13 Impact factor: 5.467