<i>In vivo</i>
            genetic evidence for klotho‐dependent, fibroblast growth factor 23 (Fgf23) ‐mediated regulation of systemic phosphate homeostasis

Nakatani, Teruyo; Sarraj, Bara; Ohnishi, Mutsuko; Densmore, Michael; Taguchi, Takashi; Goetz, Regina; Mohammadi, Moosa; Lanske, Beate; Razzaque, Mohammed S.

doi:10.1096/fj.08-114397

Cited by 231 publications

(223 citation statements)

References 40 publications

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“…Even extremely high serum FGF23 levels in mice lacking Klotho do not cause a phosphate wasting phenotype, illustrating that the absence of Klotho confers resistance to FGF23 (31). Our data concur with the concept that Klotho is required in humans to permit FGF23 to accomplish its biologic activity.…”

Section: Discussionsupporting

confidence: 86%

Soluble Klotho and Autosomal Dominant Polycystic Kidney Disease

Pavik

Jaeger

Ebner

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Fibroblast growth factor 23 (FGF23) levels are elevated in patients with autosomal dominant polycystic kidney disease (ADPKD) and X-linked hypophosphatemia (XLH), but only the latter is characterized by a renal phosphate wasting phenotype. This study explored potential mechanisms underlying resistance to FGF23 in ADPKD.Design, setting, participants, & measurements FGF23 and Klotho levels were measured, and renal phosphate transport was evaluated by calculating the ratio of the maximum rate of tubular phosphate reabsorption to GFR (TmP/GFR) in 99 ADPKD patients, 32 CKD patients, 12 XLH patients, and 20 healthy volunteers. ADPKD and CKD patients were classified by estimated GFR (CKD stage 1, $90 ml/min per 1.73 m 2 ; CKD stage 2, 60-89 ml/min per 1.73 m 2 ).Results ADPKD patients had 50% higher FGF23 levels than did XLH patients; TmP/GFR was near normal in most ADPKD patients and very low in XLH patients. Serum Klotho levels were lowest in the ADPKD group, whereas the CKD and XLH groups and volunteers had similar levels. ADPKD patients with an apparent renal phosphate leak had two-fold higher Klotho levels than those without. Serum Klotho values correlated inversely with cyst volume and kidney growth.Conclusions Loss of Klotho might be a consequence of cyst growth and constrain the phosphaturic effect of FGF23 in most patients with ADPKD. Normal serum Klotho levels were associated with normal FGF23 biologic activity in all XLH patients and a minority of ADPKD patients. Loss of Klotho and FGF23 increase appear to exceed and precede the changes that can be explained by loss of GFR in patients with ADPKD.

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Section: Discussionsupporting

confidence: 86%

Soluble Klotho and Autosomal Dominant Polycystic Kidney Disease

Pavik

Jaeger

Ebner

et al. 2012

Clinical Journal of the American Society of Nephrology

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“…In theory, the effect of NH 4 Cl treatment on the intact FGF23 levels could have contributed to the extended life span of kl/kl mice. However, according to earlier observations, 62 the growth deficit and shortened life span of klotho-deficient mice is not significantly modified by additional knockout of FGF23.…”

Section: Discussionmentioning

confidence: 71%

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

Leibrock¹,

Alesutan²,

Voelkl³

et al. 2015

Journal of the American Society of Nephrology

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Klotho, a cofactor in suppressing 1,25(OH) 2 D 3 formation, is a powerful regulator of mineral metabolism. Klotho-hypomorphic mice (kl/kl) exhibit excessive plasma 1,25(OH) 2 D 3 , Ca 2+ , and phosphate concentrations, severe tissue calcification, volume depletion with hyperaldosteronism, and early death. Calcification is paralleled by overexpression of osteoinductive transcription factor Runx2/Cbfa1, Alpl, and senescenceassociated molecules Tgfb1, Pai-1, p21, and Glb1. Here, we show that NH 4 Cl treatment in drinking water (0.28 M) prevented soft tissue and vascular calcification and increased the life span of kl/kl mice .12-fold in males and .4-fold in females without significantly affecting extracellular pH or plasma concentrations of 1,25(OH) 2 D 3 , Ca 2+ , and phosphate. NH 4 Cl treatment significantly decreased plasma aldosterone and antidiuretic hormone concentrations and reversed the increase of Runx2/Cbfa1, Alpl, Tgfb1, Pai-1, p21, and Glb1 expression in aorta of kl/kl mice. Similarly, in primary human aortic smooth muscle cells (HAoSMCs), NH 4 Cl treatment reduced phosphate-induced mRNA expression of RUNX2/CBFA1, ALPL, and senescence-associated molecules. In both kl/kl mice and phosphate-treated HAoSMCs, levels of osmosensitive transcription factor NFAT5 and NFAT5-downstream mediator SOX9 were higher than in controls and decreased after NH 4 Cl treatment. Overexpression of NFAT5 in HAoSMCs mimicked the effect of phosphate and abrogated the effect of NH 4 Cl on SOX9, RUNX2/CBFA1, and ALPL mRNA expression. TGFB1 treatment of HAoSMCs upregulated NFAT5 expression and prevented the decrease of phosphate-induced NFAT5 expression after NH 4 Cl treatment. In conclusion, NH 4 Cl treatment prevents tissue calcification, reduces vascular senescence, and extends survival of klotho-hypomorphic mice. The effects of NH 4 Cl on vascular osteoinduction involve decrease of TGFB1 and inhibition of NFAT5-dependent osteochondrogenic signaling.

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“…In vivo studies conducted on Fgf23 knockout mice have shown that bioactive FGF23 protein could significantly reduce serum phosphate level in these mutant mice. It is of particular significance that bioactive FGF23 protein failed to exert phosphate-lowering effects in Fgf23/alpha-klotho double knockout mice, 36,37 suggesting that FGF23 loses its phosphate regulating abilities without alpha-klotho. Moreover, FGF23-induced hypophosphatemia in Hyp mice is reversed to hyperphosphatemia in the Hyp mice without alpha-klotho activity (Hyp/alpha-klotho double mutant mice), despite high serum FGF23 levels in double mutant mice.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

Brown

2015

BoneKEy Reports

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Phosphate homeostasis is coordinated and regulated by complex cross-organ talk through delicate hormonal networks. Parathyroid hormone (PTH), secreted in response to low serum calcium, has an important role in maintaining phosphate homeostasis by influencing renal synthesis of 1,25-dihydroxyvitamin D, thereby increasing intestinal phosphate absorption. Moreover, PTH can increase phosphate efflux from bone and contribute to renal phosphate homeostasis through phosphaturic effects. In addition, PTH can induce skeletal synthesis of another potent phosphaturic hormone, fibroblast growth factor 23 (FGF23), which is able to inhibit renal tubular phosphate reabsorption, thereby increasing urinary phosphate excretion. FGF23 can also fine-tune vitamin D homeostasis by suppressing renal expression of 1-alpha hydroxylase (1a(OH)ase). This review briefly discusses how FGF23, by forming a bone-kidney axis, regulates phosphate homeostasis, and how its dysregulation can lead to phosphate toxicity that induces widespread tissue injury. We also provide evidence to explain how phosphate toxicity related to dietary phosphorus overload may facilitate incidence of noncommunicable diseases including kidney disease, cardiovascular disease, cancers and skeletal disorders.

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In vivo genetic evidence for klotho‐dependent, fibroblast growth factor 23 (Fgf23) ‐mediated regulation of systemic phosphate homeostasis

Cited by 231 publications

References 40 publications

Soluble Klotho and Autosomal Dominant Polycystic Kidney Disease

Soluble Klotho and Autosomal Dominant Polycystic Kidney Disease

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

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