Tissue expression and source of circulating αKlotho

Abstract

αKlotho (Klotho), a type I transmembrane protein and a coreceptor for Fibroblast Growth Factor-23, was initially thought to be expressed only in a limited number of tissues, most importantly the kidney, parathyroid gland and choroid plexus. Emerging data may suggest a more ubiquitous Klotho expression pattern which has prompted reevaluation of the restricted Klotho paradigm. Herein we systematically review the evidence for Klotho expression in various tissues and cell types in humans and other mammals, and discuss potential reasons behind existing conflicting data. Based on current literature and tissue expression atlases, we propose a classification of tissues into high, intermediate and low/absent Klotho expression. The functional relevance of Klotho in organs with low expression levels remain uncertain and there is currently limited data on a role for membrane-bound Klotho outside the kidney. Finally, we review the evidence for the tissue source of soluble Klotho, and conclude that the kidney is likely to be the principal source of circulating Klotho in physiology.

High‐intensity interval training increases myocardial levels of Klotho and protects the heart against ischaemia–reperfusion injury

“…Some studies using the RT‐PCR approaches showed low bands from cardiac Klotho expression and other studies reported an inability to detect Klotho in mouse heart (Faul et al., 2011; Ghosh, Murphy, Kishore, & Vaughan, 2013; Sato et al., 2015; Tacer et al., 2010; Yamauchi et al., 2016). However, in spite of the contradictions in the mRNA expression of Klotho in the heart tissue, on the protein level, it has been detected in the heart using the western blot techniques, at a similar molecular size to renal Klotho (Olauson, Mencke, Hillebrands, & Larsson, 2017). So, the heart could be regarded not only as a target of soluble Klotho, but also probably an organ that produces Klotho itself (Corsetti et al., 2016).…”

Glutathione peroxidase‐1 overexpression reduces oxidative stress, and improves pathology and proteome remodeling in the kidneys of old mice

“…Klotho is an anti‐aging hormone involved in senescence, endogenous antioxidants, apoptosis and phosphate homeostasis (Kuro‐o et al., 1997; Kurosu et al., 2005). Kidney tubular epithelial cells are the main source of circulating Klotho (Olauson, Mencke, Hillebrands, & Larsson, 2017). We found that full‐length membranous Klotho (designated tissue Klotho) was significantly decreased in OWT kidney tissue by ~45%, and GPX1 TG did not prevent this decrease (Figure ).…”

The association of serum soluble Klotho levels and residual diuresis and overhydration in peritoneal dialysis patients

“…1 Full-length alpha-Klotho is a single-pass transmembrane protein that exists in 2 forms, membrane and secreted Klotho, which have different functions. 2 The membrane form acts as a co-receptor for fibroblast growth factor-23 (FGF-23) and plays an important role in calcium-phosphate metabolism. 2,3 Soluble Klotho (called α-Klotho, with molecular mass 130-kDa) seems to function as a humoral factor with various biological effects, and it works independently of FGF-23 signaling.…”

“…2 The membrane form acts as a co-receptor for fibroblast growth factor-23 (FGF-23) and plays an important role in calcium-phosphate metabolism. 2,3 Soluble Klotho (called α-Klotho, with molecular mass 130-kDa) seems to function as a humoral factor with various biological effects, and it works independently of FGF-23 signaling. 4 Among the pleiotropic actions that soluble Klotho is responsible for are tissue protection from oxidative stress, fibrosis and apoptotic stimuli; regulation of blood phosphate and vitamin D3 levels; and the activity of multiple cell surface calcium and potassium ion channels.…”

“…4 Among the pleiotropic actions that soluble Klotho is responsible for are tissue protection from oxidative stress, fibrosis and apoptotic stimuli; regulation of blood phosphate and vitamin D3 levels; and the activity of multiple cell surface calcium and potassium ion channels. 2,3,5 There are data suggesting that secreted Klotho exerts phosphaturic effects independently of FGF-23. 3 Soluble Klotho has also been associated with protective effects against vascular calcification.…”