Cellular and Molecular Life Sciences

, Volume 76, Issue 23, pp 4705–4724 | Cite as

αKlotho–FGF23 interactions and their role in kidney disease: a molecular insight

  • Edward R. SmithEmail author
  • Stephen G. Holt
  • Tim D. Hewitson


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.


Fibroblast growth factor Klotho proteins structural biology Crystallography Kidney disease Cardiovascular disease Receptors Therapeutics Phosphate 



The authors were supported by a Grant-in-Aid (GIA-021-2017) from the RMH Home Lottery Research Fund. The figures in this review were partly generated using vector images freely available from Servier Medical Art ( which is licensed under a Creative Commons Attribution 3.0 Unported License.

Author contributions

ERS, TDH: manuscript drafting, revision and final approval.

Compliance with ethical standards

Conflict of interest

The authors declare they have no relevant conflicts of interest.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of NephrologyThe Royal Melbourne HospitalMelbourneAustralia
  2. 2.Department of MedicineUniversity of MelbourneParkvilleAustralia

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