αKlotho-FGF23 interactions and their role in kidney disease: a molecular insight.
Following the serendipitous discovery of the ageing suppressor, αKlotho (αKl), several decades ago, a growing body of evidence has defined a pivotal role for its various forms in multiple aspects of vertebrate physiology and pathology. The transmembrane form of αKl serves as a co-receptor for the osteocyte-derived mineral regulator, fibroblast growth factor (FGF)23, principally in the renal tubules. However, compelling data also suggest that circulating soluble forms of αKl, derived from the same source, may have independent homeostatic functions either as a hormone, glycan-cleaving enzyme or lectin. Chronic kidney disease (CKD) is of particular interest as disruption of the FGF23-αKl axis is an early and common feature of disease manifesting in markedly deficient αKl expression, but FGF23 excess. Here we critically discuss recent findings in αKl biology that conflict with the view that soluble αKl has substantive functions independent of FGF23 signalling. Although the issue of whether soluble αKl can act without FGF23 has yet to be resolved, we explore the potential significance of these contrary findings in the context of CKD and highlight how this endocrine pathway represents a promising target for novel anti-ageing therapeutics.
['Smith|Edward R|ER|http://orcid.org/0000-0002-2651-1787', 'Holt|Stephen G|SG|http://orcid.org/0000-0001-5004-5539', 'Hewitson|Tim D|TD|http://orcid.org/0000-0002-1994-2423']
D000818:Animals D000089703:Fibroblast Growth Factor-23 D005346:Fibroblast Growth Factors D005966:Glucuronidase D006801:Humans D017379:Hypertrophy, Left Ventricular D007674:Kidney Diseases D000090265:Klotho Proteins D000072417:Protein Domains D020794:Receptor Protein-Tyrosine Kinases D051436:Renal Insufficiency, Chronic D015398:Signal Transduction
Kidney disease Fibroblast growth factor Therapeutics Cardiovascular disease Crystallography Klotho proteins structural biology Phosphate Receptors