Involvement of α-klotho in growth hormone (GH) signaling.

Growth hormone (GH) exerts multiple effects on different organs directly or via its main mediator, insulin-like growth factor1 (IGF1). In this study, we focused on the novel relationship between GH action and the antiaging hormone α-klotho. Immunofluorescent staining of α-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 IGF1 mRNA expression in the pituitary gland, liver, heart, kidney, and bone but increased α-klotho mRNA expression only in the pituitary gland, kidney, and bone. Increased α-klotho protein levels were observed in the kidney but not in the pituitary gland. No induction of α-klotho RNA expression by GH was observed in juvenile mice with kidney disease, indicating GH resistance. Furthermore, GH and α-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 α-klotho, which is detected in blood by the downstream action of GH, 2) α-klotho induction by GH is resistant in kidney disease, and 3) α-klotho might be an enhanced regulator of GH signaling.

Effects of EOS789, a novel pan-phosphate transporter inhibitor, on phosphate metabolism : Comparison with a conventional phosphate binder.

BACKGROUND: Inorganic phosphate (Pi) binders are the only pharmacologic treatment approved for hyperphosphatemia. However, Pi binders induce the expression of intestinal Pi transporters and have limited effects on the inhibition of Pi transport. EOS789, a novel pan-Pi transporter inhibitor, reportedly has potent efficacy in treating hyperphosphatemia. We investigated the properties of EOS789 with comparison to a conventional Pi binder. METHODS: Protein and mRNA expression levels of Pi transporters were measured in intestinal and kidney tissues from male Wistar rats fed diets supplemented with EOS789 or lanthanum carbonate (LC). 32Pi permeability was measured in intestinal tissues from normal rats using a chamber. RESULTS: Increased protein levels of NaPi-2b, an intestinal Pi transporter, and luminal Pi removal were observed in rats treated with LC but not in rats treated with EOS789. EOS789 but not LC suppressed intestinal protein levels of the Pi transporter Pit-1 and sodium/hydrogen exchanger isoform 3. 32Pi flux experiments using small intestine tissues from rats demonstrated that EOS789 may affect transcellular Pi transport in addition to paracellular Pi transport. CONCLUSION: EOS789 has differing regulatory effects on Pi metabolism compared to LC. The properties of EOS789 may compensate for the limitations of LC therapy. The combined or selective use of EOS789 and conventional Pi binders may allow tighter control of hyperphosphatemia. J. Med. Invest. 70 : 260-270, February, 2023.