Klotho Lacks a Vitamin D Independent Physiological Role in Glucose Homeostasis, Bone Turnover, and Steady-State PTH Secretion In Vivo

Abstract

Apart from its function as co-receptor for fibroblast growth factor-23 (FGF23), Klotho is thought to regulate insulin signaling, intracellular oxidative stress, and parathyroid hormone (PTH) secretion in an FGF23 independent fashion. Here, we crossed Klotho deficient (Kl−/−) mice with vitamin D receptor (VDR) mutant mice to examine further vitamin D independent functions of Klotho. All mice were fed a rescue diet enriched with calcium, phosphorus, and lactose to prevent hyperparathyroidism in VDR mutants, and were killed at 4 weeks of age after double fluorochrome labeling. Kl−/− mice displayed hypercalcemia, hyperphosphatemia, dwarfism, organ atrophy, azotemia, pulmonary emphysema, and osteomalacia. In addition, glucose and insulin tolerance tests revealed hypoglycemia and profoundly increased peripheral insulin sensitivity in Kl−/− mice. Compound mutants were normocalcemic and normophosphatemic, did not show premature aging or organ atrophy, and were phenocopies of VDR mutant mice in terms of body weight, bone mineral density, bone metabolism, serum calcium, serum phosphate, serum PTH, gene expression in parathyroid glands, as well as urinary calcium and phosphate excretion. Furthermore, ablation of vitamin D signaling in double mutants completely normalized glucose and insulin tolerance, indicating that Klotho has no vitamin D independent effects on insulin signaling. Histomorphometry of pancreas islets showed similar beta cell volume per body weight in all groups of animals. In conclusion, our findings cast doubt on a physiologically relevant vitamin D and Fgf23 independent function of Klotho in the regulation of glucose metabolism, bone turnover, and steady-state PTH secretion in vivo.

Elevated serum 1,25(OH)2-vitamin D3 level attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in kl/kl mice

“…A vitamin D-free diet (D-diet) has been reported to maintain phosphate homeostasis and improve the kl/kl phenotype89. In this study, we fed kl/kl mice on a D-diet to determine whether the decreased vitamin D level could enhance UUO-induced RTF.…”

“…FGF23, a member of the fibroblast growth factor (FGF) family, is a bone-derived hormone that exerts its function in the kidneys, to help maintain homeostasis in phosphate and vitamin D metabolism by regulating the sodium phosphate co-transporter and the key enzymes for vitamin D metabolism CYP27B1 and CYP24A15678. Similar to FGF23-deficient mice, kl/kl mice also exhibit hyperphosphatemia and an increased serum 1,25 (OH) 2 vitamin D 3 level1, which are suspected to be the primary cause of premature aging because restricting vitamin D intake improves the kl/kl phenotype89. Secreted Klotho is formed via either alternative splicing of the gene or shedding of the extracellular domain into the extracellular space and subsequently into the circulation210.…”

Infection and smoking are associated with decreased plasma concentration of the anti-aging protein, α-klothoa

“…Membrane bound klotho also plays an integral part in the regulation of phosphate, calcium and vitamin D homeostasis in human and mice[2, 5, 8, 84, 136, 190]. Lack of expression in either klotho or FGF23 result in phosphate retention and a premature-aging syndrome in the mouse[94, 101, 128, 146, 147].…”

“…Prior studies have focused on the roles of Klotho in chronic renal disorders[37, 74-76, 142, 178, 184, 214], disorders of calcium metabolism[2, 5, 8, 73, 82, 84, 190], hypertension,[33, 123, 132, 175, 197] and aging[49, 93, 96, 109, 187, 191]. Kuro-o et al demonstrated that klotho is also expressed in the placenta; however, of pregnancy complications has not been investigated [96].…”

Regulation of the Voltage Gated K⁺ Channel K_v1.3 by Recombinant Human Klotho Protein

“…Klotho deficiency increases plasma 1,25(OH) 2 D 3 , Ca 2+ and phosphate [18,19] concentration, resulting in vascular calcification [20], growth deficit [2] and rapid aging [2,9,10]. Klotho insufficiency further leads to a wide variety of disorders including hypoglycemia, hearing loss, cardiac arrhythmia, sudden cardiac death, and compromised immune response [1,21,22]. …”