Alpha Klotho and phosphate homeostasis

Abstract

The Klotho family consists of three single-pass transmembrane proteins—αKlotho, βKlotho and γKlotho. Each of them combines with fibroblast growth factor (FGF) receptors (FGFRs) to form receptor complexes for various FGF’s. αKlotho is a co-receptor for physiological FGF23 signaling and appears essential for FGF23-mediated regulation of mineral metabolism. αKlotho protein also plays a FGF23-independent role in phosphate homeostasis. Animal experimental studies and clinical observations have demonstrated that αKlotho deficiency leads to severe hyperphosphatemia; moderate elevation of αKlotho reduces serum phosphate and extremely high αKlotho induces hypophosphatemia and high-FGF23. αKlotho maintains circulating phosphate in a narrow range by modulating intestinal phosphate absorption, urinary phosphate excretion by the kidney, and phosphate distribution into bone rather than soft tissue in concerted interaction with other calciophosphotropic hormones such as PTH, FGF23, and 1,25-(OH)2 vitamin D. The role of αKlotho in maintenance of phosphate homeostasis is mediated by direct suppression of Na-dependent phosphate cotransporters in target organs. Therefore, αKlotho manipulation may be a novel strategy for genetic and acquired phosphate disorders and for medical conditions with αKlotho deficiency such as chronic kidney disease in future.

Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy

“…Note that α-Klotho also reduced plasma phosphate in sham-treated mice fed a high-phosphate diet (Figure 3b), supporting α-Klotho’s role as a phosphaturic substance. 17,26 Recombinant α-Klotho protein improved Cl Cr and reduced blood urea nitrogen in both CKD and sham-treated mice fed with high phosphate (Figure 3c and d), indicating that recombinant α-Klotho protein preserved renal function. Furthermore, α-Klotho–treated CKD mice and sham-treated mice fed a high-phosphate diet, respectively, both had lower plasma iFGF23 and cFGF23 and higher plasma α-Klotho than did vehicle-treated CKD mice and sham-treated mice fed a high-phosphate diet, respectively (Figure 3e–g).…”

“…18 α-Klotho also improves phosphate homeostasis, which in turn is also associated with retardation of CKD progression. 11,12,26 In addition, α-Klotho suppressed transient receptor potential channel 6in podocytes, ameliorated albuminuria by protecting the glomerular filter, and retarded CKD progression. 39 α-Klotho–dependent tissue recovery after injury may be associated with preservation of stem cells.…”

A Nomogram to Predict Contrast Induced Nephropathy in Patients Undergoing Percutaneous Coronary Intervention

“…15) At the cellular level, sklotho exerts its renal protective property by reducing oxidative stress and improving endothelial function. 16) Emerging experimental and clinical evidence indicates that during the progression of AKI from diverse etiologies, sklotho decreases significantly in the early phase.…”

αKlotho and Chronic Kidney Disease

“…FGF23, a phosphatonin, is thought to be implicated in the systemic balance of phosphate maintained by the interaction of intestine, bone, and kidneys (Hu, Shiizaki, Kuro-o, et al, 2013) through interplay with αKlotho, parathyroid hormone (PTH), and 1,25-(OH) 2 -vitamin D 3 (Bian, Xing, & Hu, 2014). One principal stimulus for FGF23 secretion is currently believed to be high serum phosphate caused by dietary phosphate load (Nishida et al, 2006).…”