FGF23 Actions on Target Tissues—With and Without Klotho

Abstract

Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in “classic” klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23’s potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might—at least partially—underlie the pleiotropic tissue-protective functions of klotho.

Dysregulated Mineral Metabolism in AKI

“…43 In addition, increased levels of PTH and FGF23 and reduced levels of klotho and 1,25D also likely contribute to the development of other comorbidities common in CKD, including anemia, chronic inflammation, immune dysfunction, and left ventricular hypertrophy. 44,45 Consistent with these data, epidemiologic studies consistently have shown that abnormalities in mineral metabolites, including increased circulating FGF23 and decreased vitamin D metabolite levels, are strong and independent predictors of cardiovascular and all-cause mortality in CKD patients. 46,47 Targeting these abnormalities pharmacologically and otherwise as a strategy to improve outcomes in CKD therefore has been an area of active investigation for decades.…”

Role of αKlotho and FGF23 in regulation of type II Na-dependent phosphate co-transporters

“…FGF23 at high concentration also directly inhibits NaPi-2a protein in renal tubules through a non-canonical αKlotho independent signaling pathway [2], which still needs to be defined. In the heart, FGF23 has been proposed to trans-activate the FGFR4 [35, 77]. …”

Fibroblast Growth Factor 23 and Klotho in AKI

“…For example, the heart was shown to express Fgf23 mRNA in a model of acute myocardial infarction, the liver was shown to express Fgf23 mRNA in a liver fibrosis model, and the kidneys were shown to produce both Fgf23 mRNA and protein in a number of chronic injury animal models. 26,28,35,53 Leaf et al 54 also showed FGF23 protein expression by immunohistochemistry performed on colonic adenocarcinoma tissue obtained from a patient with stage IV colon cancer who presented with oncogenic osteomalacia. In each of these models and settings, the pleiotropic production of FGF23 was linked to increased circulating FGF23 levels, although the significance of this production in mediating the adverse effects of increased FGF23 is unknown.…”