Dietary-Supplemented Zinc Positively Induces αKlotho Expression and Affects Growth Hormone Action in CKD

Background: The α-klotho identified in α-klotho mutant mice (kl/kl mice) exhibiting symptoms of early aging and exists in membrane and secreted forms. The kl/kl mice show a reduced number of vesicles in growth hormone-producing cells, resulting in growth hormone resistance and no weight gain after growth hormone administration. Growth Hormone (GH) is secreted from the anterior pituitary gland and exerts various metabolic functions via insulin-like growth factor 1 (IGF1), which is produced mainly in the liver. In pediatric GH deficiency, secretory α-klotho blood levels are reduced, and GH treatment increases blood levels. Chronic kidney disease (CKD) in children is also associated with alterations in the GH/IGF1 axis, including impaired GH signaling and growth retardation associated with GH-resistance. In the present study, we focused on the relationship between GH action and the anti-ageing hormone. And we hypothesized that a-klotho deficiency may contribute to GH resistance in CKD. Methods: Growth hormone (4mg/kg B.W) was administered to 4-week-old mice and a model of adenine-induced pediatric kidney disease mice. Results: We investigated the induction of α-klotho expression following GH administration in mice. GH increased the expression of a-klotho mRNA in the kidney, pituitary gland, femur, and calvaria. Particularly in the kidney and blood, GH administration led to an increase in α-klotho protein expression.Next, mice models of adenine-induced pediatric kidney disease were generated and treated with GH, but no induction of GH receptor, IGF1, and α-klotho mRNA expression was observed, indicating GH resistance, suggesting that reduced α-klotho expression may suppress GH action. α-klotho maintenance and increase could improve GH resistance, we investigated nutrients that increase α-klotho expression, and found that zinc increased α-klotho expression in the kidney without inhibiting growth. Finally, mice modeling kidney disease were treated with a zinc-supplemented diet for 3 weeks, followed by GH. In the zinc-supplemented diet group, an increase in renal α-klotho and IGF1 mRNA expression was observed and a recovery of growth inhibition was observed compared to the normal diet group. Conclusion: α-klotho is downstream of GH, suggesting that it may be involved in GH resistance in CKD. Funding: Government Support – Non-U.S.