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Central role of the proximal tubular ?Klotho/FGF receptor complex in FGF23-regulated phosphate and vitamin D metabolism.

ABSTRACT: Fibroblast growth factor 23 (FGF23) plays critical roles in phosphate handling and vitamin D metabolism in the kidney. However, the effector cells of FGF23 in the kidney remain unclear. ?Klotho, a putative enzyme possessing ?-glucuronidase activity and also a permissive co-receptor for FGF23 to bind to FGF receptors (FGFRs), is expressed most abundantly in distal convoluted tubules, whereas it is expressed modestly in proximal tubules. Key molecular players of phosphate homeostasis and vitamin D-metabolizing enzymes are known to localize in proximal tubules. To clarify the direct function of FGF23 on proximal tubules, we ablated ?Klotho or Fgfr1-4 genes specifically from these tubules using the Cre-loxP-mediated genetic recombination. Both conditional knockout mouse lines showed similar phenotypes that resembled those of systemic ?Klotho or Fgf23 knockout mice. Compared with control mice, they showed significantly elevated levels of plasma phosphate, FGF23 and 1,25-dihydroxyvitamin D, ectopic calcification in the kidney and aging-related phenotypes like growth retardation, osteoporosis and shortened lifespan. These findings suggest that the primary function of FGF23 on mineral metabolism is mediated through ?Klotho/FGFR co-receptors expressed in proximal tubular cells, and that the putative enzymatic function of ?Klotho in the proximal tubule has a minor role in systemic mineral metabolism.

SUBMITTER: Takeshita A

PROVIDER: S-EPMC5932018 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Central role of the proximal tubular αKlotho/FGF receptor complex in FGF23-regulated phosphate and vitamin D metabolism.

Takeshita Ai A Kawakami Kazuki K Furushima Kenryo K Miyajima Masayasu M Sakaguchi Kazushige K

Scientific reports 20180502 1

Fibroblast growth factor 23 (FGF23) plays critical roles in phosphate handling and vitamin D metabolism in the kidney. However, the effector cells of FGF23 in the kidney remain unclear. αKlotho, a putative enzyme possessing β-glucuronidase activity and also a permissive co-receptor for FGF23 to bind to FGF receptors (FGFRs), is expressed most abundantly in distal convoluted tubules, whereas it is expressed modestly in proximal tubules. Key molecular players of phosphate homeostasis and vitamin D ...[more]

PMID: 29720668

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Project description:Background and objectivesThe estimated glomerular filtration rate (eGFR) is a crucial parameter in heart failure. Much less is known about the importance of tubular function. We addressed the effect of tubular maximum phosphate reabsorption capacity (TmP/GFR), a parameter of proximal tubular function, in patients with heart failure.Design, setting, participants, & measurementsWe established TmP/GFR (Bijvoet formula) in 2085 patients with heart failure and studied its association with deterioration of kidney function (>25% eGFR decrease from baseline) and plasma neutrophil gelatinase-associated lipocalin (NGAL) doubling (baseline to 9 months) using logistic regression analysis and clinical outcomes using Cox proportional hazards regression. Additionally, we evaluated the effect of sodium-glucose transport protein 2 (SGLT2) inhibition by empagliflozin on tubular maximum phosphate reabsorption capacity in 78 patients with acute heart failure using analysis of covariance.ResultsLow TmP/GFR (<0.80 mmol/L) was observed in 1392 (67%) and 21 (27%) patients. Patients with lower TmP/GFR had more advanced heart failure, lower eGFR, and higher levels of tubular damage markers. The main determinant of lower TmP/GFR was higher fractional excretion of urea (P<0.001). Lower TmP/GFR was independently associated with higher risk of plasma NGAL doubling (odds ratio, 2.20; 95% confidence interval, 1.05 to 4.66; P=0.04) but not with deterioration of kidney function. Lower TmP/GFR was associated with higher risk of all-cause mortality (hazard ratio, 2.80; 95% confidence interval, 1.37 to 5.73; P=0.005), heart failure hospitalization (hazard ratio, 2.29; 95% confidence interval, 1.08 to 4.88; P=0.03), and their combination (hazard ratio, 1.89; 95% confidence interval, 1.07 to 3.36; P=0.03) after multivariable adjustment. Empagliflozin significantly increased TmP/GFR compared with placebo after 1 day (P=0.004) but not after adjustment for eGFR change.ConclusionsTmP/GFR, a measure of proximal tubular function, is frequently reduced in heart failure, especially in patients with more advanced heart failure. Lower TmP/GFR is furthermore associated with future risk of plasma NGAL doubling and worse clinical outcomes, independent of glomerular function.

Dataset Information

Central role of the proximal tubular ?Klotho/FGF receptor complex in FGF23-regulated phosphate and vitamin D metabolism.

Publications

Central role of the proximal tubular αKlotho/FGF receptor complex in FGF23-regulated phosphate and vitamin D metabolism.

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