Dataset Information

Renal Production, Uptake, and Handling of Circulating ?Klotho.

ABSTRACT: ?Klotho is a multifunctional protein highly expressed in the kidney. Soluble ?Klotho is released through cleavage of the extracellular domain from membrane ?Klotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating ?Klotho production and handling is incompletely understood, however. Here, we found higher ?Klotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum ?Klotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of ?Klotho extracellular domain shedding. Furthermore, the serum half-life of exogenous ?Klotho in anephric rats was four- to five-fold longer than that in normal rats, and exogenously injected labeled recombinant ?Klotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and in vitro (proximal tubule cell line) studies showed that ?Klotho traffics from the basal to the apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in ?Klotho homeostasis, producing and releasing ?Klotho into the circulation and clearing ?Klotho from the blood into the urinary lumen.

SUBMITTER: Hu MC

PROVIDER: S-EPMC4696570 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Publications

Renal Production, Uptake, and Handling of Circulating αKlotho.

Hu Ming Chang MC Shi Mingjun M Zhang Jianning J Addo Tayo T Cho Han Ju HJ Barker Sarah L SL Ravikumar Priya P Gillings Nancy N Bian Ao A Sidhu Sachdev S SS Kuro-o Makoto M Moe Orson W OW

Journal of the American Society of Nephrology : JASN 20150514 1

αKlotho is a multifunctional protein highly expressed in the kidney. Soluble αKlotho is released through cleavage of the extracellular domain from membrane αKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating αKlotho production and handling is incompletely understood, however. Here, we found higher αKlotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum αKlotho concentration dr ...[more]

PMID: 25977312

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Project description:Excess fibroblast growth factor 23 (FGF23), excess PTH, and an increase in extracellular calcium cause hypophosphatemia by lowering the maximum renal phosphate reabsorption threshold (TmP/GFR). We recently reported two cases of X-linked hypophosphatemia (XLH) with severe tertiary hyperparathyroidism who had normalization of TmP/GFR upon being rendered hypoparathyroid following total parathyroidectomy, despite marked excess in both C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23). We explored the effects of FGF23, PTH, and calcium on TmP/GFR in a cross-sectional study (n =?74) across a spectrum of clinical cases with abnormalities in TmP/GFR, PTH, and FGF23. This comprised three groups: FGF23-dependent hypophosphatemia (n =?27), hypoparathyroidism (HOPT; n =?17), and chronic kidney disease (n =?30). Measurements included TmP/GFR, cFGF23, PTH, ionized calcium, vitamin D metabolites, and bone turnover markers. The combined effect of cFGF23, PTH, and ionized calcium on TmP/GFR was modeled using hierarchical multiple regression and was probed by moderation analysis with PROCESS. Modeling analysis showed independent effects on TmP/GFR by cFGF23, PTH, and ionized calcium in conjunction with a weak but significant effect of the interaction term for PTH and FGF23; probing showed that the effect was most prominent during PTH deficiency. Teriparatide 20??g daily was self-administered for 28?days by one case of X-linked hypophosphatemia with hypoparathyroidism (XLH-HOPT) to assess the response of TmP/GFR, cFGF23, iFGF23, nephrogenous cyclic adenosine monophosphate (NcAMP), vitamin D metabolites, and bone turnover markers. After 28?days, TmP/GFR was lowered from 1.10?mmol/L to 0.48?mmol/L; this was accompanied by increases in NcAMP, ionized calcium, and bone turnover markers. In conclusion, the effect of FGF23 excess on TmP/GFR is altered by PTH such that the effect is ameliorated by hypoparathyroidism and the effect is augmented by hyperparathyroidism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Dataset Information

Renal Production, Uptake, and Handling of Circulating ?Klotho.

Publications

Renal Production, Uptake, and Handling of Circulating αKlotho.

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