Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease

Abstract

Background: Membrane αKlotho (hereinafter called Klotho) is highly expressed in the kidney and functions as a coreceptor of FGF receptors (FGFRs) to activate specific fibroblast growth factor 23 (FGF23) signal pathway. FGF23 is produced in bones and participates in the maintenance of mineral homeostasis. The extracellular domain of transmembrane Klotho can be cleaved by secretases and released into the circulation as soluble Klotho. Soluble Klotho does not only weakly activate FGFRs to transduce the FGF23 signaling pathway, but also functions as an enzyme and hormonal substance to play a variety of biological functions. FGF23 exerts its biological effects through activation of FGFRs in a Klotho-dependent manner. However, extremely high FGF23 can exert its pathological action in a Klotho-independent manner.

Summary: The decline in serum and urinary Klotho followed by a rise in serum FGF23 at an early stage of chronic kidney disease (CKD) functions as an early biomarker for kidney dysfunction and can also serve as a predictor for risk of cardiovascular disease (CVD) and mortality in both CKD patients and the general population. Moreover, Klotho deficiency is a pathogenic factor for CKD progression and CVD. FGF23 may also contribute to CVD. Prevention of Klotho decline, reactivation of endogenous Klotho production, or supplementation of exogenous Klotho attenuate renal fibrosis, retard CKD progression, improve mineral metabolism, ameliorate cardiomyopathy, and alleviate vascular calcification in CKD. However, the poor CVD outcome after depletion of FGF23 with FGF23 antibody stimulates the generation of a more specific inhibitor of FGF23 for CKD treatment.

Key message: Klotho/FGF23 may not only be diagnostic and/or prognostic biomarkers for CKD and CVD, but are also pathogenic contributors to CKD progression and CVD development. The Klotho/FGF23 axis should be a novel target for renal clinics.

Keywords: Biomarker; Cardiovascular disease; Chronic kidney disease; FGF23; Klotho.

Fig. 1

Source of soluble Klotho. The kidney is the main source of circulating Klotho under physiological conditions. Both renal proximal and distal tubules express membrane Klotho protein and also presumably produce secreted Klotho protein through alternative splicing. The secreted Klotho only contains a Kl1 domain and is directly secreted into the blood circulation (left panel); its biological function is not completely clear yet. Extracellular domain of membrane Klotho containing Kl1 and Kl2 repeats is shed and cleaved by secretases into either full extracellular domain or Kl1 repeat, and directly exerts its biological actions. Both cleaved Klotho fragments are in the blood circulation (right panel).

Fig. 2

Proposed modes of fibroblast growth factor 23 (FGF23) and Klotho action. Membrane Klotho (green) binds to the FGF receptor (FGFR) (brown), which in turn binds to FGF23 (white and pink) to form the 2FGF23/2FGFR2/Klotho complex. In this complex, Klotho functions as the receptor to replace the function of heparan sulfate to transduce the FGF23 signal. The potential FGFRs for FGF23 include FGFR1c, FGFR3c, and FGFR4 and serve as the high-affinity receptor for FGF23 (left panel). Soluble Klotho may form a similar complex and potentially prevent high FGF23-induced side (off-target) effects (middle panel). Soluble Klotho also exerts its multiple biological actions in an FGF23-independent manner via a yet-to-be-identified mechanism(s) (right panel).

Fig. 3

Proposed model and time profile of changes in serum Klotho, fibroblast growth factor 23 (FGF23), phosphate (Pi), and hormones relevant to mineral metabolism in relation to chronic kidney disease (CKD) progression. The decline in Klotho (black line) is an early event which is followed by other changes as CKD progresses. Low Klotho may induce FGF23 resistance causing a compensatory increase in blood FGF23 levels (red line) to maintain Pi homeostasis in CKD. The compensatory increase in FGF23 then suppresses 1,25-(OH)₂-vitamin D₃ (1,25-(OH)₂D₃) production (blue line). Low 1,25-(OH)₂D₃ and high blood Pi (purple line) due to progressive decline in renal function increase parathyroid hormone (PTH) (green line), which may contribute to high FGF23 in advanced CKD.