Conditional Deletion of Fgfr1 in the Proximal and Distal Tubule Identifies Distinct Roles in Phosphate and Calcium Transport

Han, Xiaobin; Yang, Juhua; Li, Linqiang; Huang, Jinsong; King, Gwendalyn D.; Quarles, L. Darryl

doi:10.1371/journal.pone.0147845

Cited by 61 publications

(74 citation statements)

References 50 publications

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“…Our finding that the phosphaturic effect of FGF23 is based on a direct action on proximal tubules is strongly supported by two recent reports: i) Han and coworkers [37] showed that mice with a specific deletion of Fgfr1 in proximal renal tubules are characterized by hyperphosphatemia and show resistance to the phosphaturic effect of FGF23. ii) Ide and coworkers [38] reported that mice with a specific deletion of Klotho in proximal tubules were unable to increase renal phosphate excretion in response to a high phosphate diet.…”

Section: Proximal Tubular Phosphate Re-uptakesupporting

confidence: 89%

“…Taken together, our recent findings demonstrate that FGF23, similar to the other phosphaturic hormone PTH, also acts as a calcium-conserving hormone in the distal nephron. This notion has recently been independently confirmed: similar to our Klotho and Fgf23 loss-of-function models, conditional knockout mice with a specific deletion of Fgfr1 in distal renal tubules are characterized by renal calcium wasting [37].…”

Section: Distal Tubular Calcium and Sodium Transportsupporting

confidence: 65%

“…ii) Ide and coworkers [38] reported that mice with a specific deletion of Klotho in proximal tubules were unable to increase renal phosphate excretion in response to a high phosphate diet. The study by Han et al [37] also sheds light on the question which FGF receptor is mainly mediating the phosphaturic actions of FGF23 signaling. Proximal tubular epithelial cells express FGFR1, 3, and 4, but not 2 [17,39].…”

Section: Proximal Tubular Phosphate Re-uptakementioning

confidence: 97%

“…Proximal tubular epithelial cells express FGFR1, 3, and 4, but not 2 [17,39]. Since conditional ablation of Fgfr1 in proximal renal tubules largely blunts the hypophosphatemic action of FGF23 [37], FGFR1 is probably the predominant receptor responsible for the FGF23-mediated increase in urinary phosphate excretion in vivo, confirming earlier studies which compared the hypophosphatemic action of FGF23 in global Fgfr4 or Fgfr3 deficient mice and kidney specific Fgfr1 knockout mice [39]. However, ablation of both Fgfr1 and Fgfr4 is necessary to completely abolish the phosphaturic action of FGF23 in mice [40], suggesting that FGFR4 also plays some, albeit minor role for FGF23-induced regulation of phosphate co-transporters in the kidney in vivo.…”

Section: Proximal Tubular Phosphate Re-uptakementioning

confidence: 99%

“…Regarding the FGF receptors responsible for the FGF23-mediated suppression of renal 1α-hydroxylase, it has recently been shown that treatment with recombinant FGF23 fails to induce a decrease in serum 1,25(OH) 2 D levels in mice with a conditional deletion of Fgfr1 in proximal tubules, indicating that, similar to the suppression of phosphate reabsorption by FGF23, FGFR1 may be the most important FGFR for the FGF23-mediated regulation of 1,25(OH) 2 D production in proximal tubules [37]. In contrast, earlier studies using kidney-specific conditional Fgfr1 knockout mice, as well as global Fgfr3 −/− and Fgfr4 −/− mutants treated with recombinant FGF23 showed a similar suppression of serum 1,25(OH) 2 D levels by FGF23 in all three knockout lines [39], suggesting that more than one FGFR may mediate the effect of FGF23 on 1,25(OH) 2 D metabolism.…”

Section: Proximal Tubular Vitamin D Hormone Synthesismentioning

confidence: 99%

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FGF23-Klotho signaling axis in the kidney

Erben

Andrukhova

2017

Bone

122

106

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Fibroblast growth factor-23 (FGF23) is a bone-derived hormone protecting against the potentially deleterious effects of hyperphosphatemia by suppression of phosphate reabsorption and of active vitamin D hormone synthesis in the kidney. The kidney is one of the main target organs of FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23-Klotho signaling in the kidney. During recent years, it has become clear that FGF23 acts independently on proximal and distal tubular epithelium. In proximal renal tubules, FGF23 suppresses phosphate reabsorption by a Klotho dependent activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and of serum/glucocorticoid-regulated kinase-1 (SGK1), leading to phosphorylation of the scaffolding protein Na/H exchange regulatory cofactor (NHERF)-1 and subsequent internalization and degradation of sodium-phosphate cotransporters. In distal renal tubules, FGF23 augments calcium and sodium reabsorption by increasing the apical membrane expression of the epithelial calcium channel TRPV5 and of the sodium-chloride cotransporter NCC through a Klotho dependent activation of with-no-lysine kinase-4 (WNK4). In proximal and distal renal tubules, FGF receptor-1 is probably the dominant FGF receptor mediating the effects of FGF23 by forming a complex with membrane-bound Klotho in the basolateral membrane. The newly described sodium- and calcium-conserving functions of FGF23 may have major implications for the pathophysiology of diseases characterized by chronically increased circulating FGF23 concentrations such as chronic kidney disease.

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Section: Proximal Tubular Phosphate Re-uptakesupporting

confidence: 89%

Section: Distal Tubular Calcium and Sodium Transportsupporting

confidence: 65%

Section: Proximal Tubular Phosphate Re-uptakementioning

confidence: 97%

Section: Proximal Tubular Phosphate Re-uptakementioning

confidence: 99%

Section: Proximal Tubular Vitamin D Hormone Synthesismentioning

confidence: 99%

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FGF23-Klotho signaling axis in the kidney

Erben

Andrukhova

2017

Bone

122

106

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Mechanisms and Regulation of Intestinal Phosphate Absorption

Hernando¹,

Wagner²

2018

Comprehensive Physiology

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States of hypo- and hyperphosphatemia have deleterious consequences including rickets/osteomalacia and renal/cardiovascular disease, respectively. Therefore, the maintenance of appropriate plasma levels of phosphate is an essential requirement for health. This control is executed by the collaborative action of intestine and kidney whose capacities to (re)absorb phosphate are regulated by a number of hormonal and metabolic factors, among them parathyroid hormone, fibroblast growth factor 23, 1,25(OH) vitamin D , and dietary phosphate. The molecular mechanisms responsible for the transepithelial transport of phosphate across enterocytes are only partially understood. Indeed, whereas renal reabsorption entirely relies on well-characterized active transport mechanisms of phosphate across the renal proximal epithelia, intestinal absorption proceeds via active and passive mechanisms, with the molecular identity of the passive component still unknown. The active absorption of phosphate depends mostly on the activity and expression of the sodium-dependent phosphate cotransporter NaPi-IIb (SLC34A2), which is highly regulated by many of the factors, mentioned earlier. Physiologically, the contribution of NaPi-IIb to the maintenance of phosphate balance appears to be mostly relevant during periods of low phosphate availability. Therefore, its role in individuals living in industrialized societies with high phosphate intake is probably less relevant. Importantly, small increases in plasma phosphate, even within normal range, associate with higher risk of cardiovascular disease. Therefore, therapeutic approaches to treat hyperphosphatemia, including dietary phosphate restriction and phosphate binders, aim at reducing intestinal absorption. Here we review the current state of research in the field. © 2017 American Physiological Society. Compr Physiol 8:1065-1090, 2018.

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FGF23 and Vitamin D Metabolism

Latic

Erben

2021

JBMR Plus

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Apart from its phosphaturic action, the bone-derived hormone fibroblast growth factor-23 (FGF23) is also an essential regulator of vitamin D metabolism. The main target organ of FGF23 is the kidney, where FGF23 suppresses transcription of the key enzyme in vitamin D hormone (1,25(OH) 2 D) activation, 1α-hydroxylase, and activates transcription of the key enzyme responsible for vitamin D degradation, 24-hydroxylase, in proximal renal tubules. The circulating concentration of 1,25(OH) 2 D is a positive regulator of FGF23 secretion in bone, forming a feedback loop between kidney and bone. The importance of FGF23 as regulator of vitamin D metabolism is underscored by the fact that in the absence of FGF23 signaling, the tight control of renal 1α-hydroxylase fails, resulting in overproduction of 1,25(OH) 2 D in mice and men. During recent years, big strides have been made toward a more complete understanding of the mechanisms underlying the FGF23-mediated regulation of vitamin D metabolism, especially at the genomic level. However, there are still major gaps in our knowledge that need to be filled by future research. Importantly, the intracellular signaling cascades downstream of FGF receptors regulating transcription of 1α-hydroxylase and 24-hydroxylase in proximal renal tubules still remain unresolved. The purpose of this review is to highlight our current understanding of the molecular mechanisms underlying the regulation of vitamin D metabolism by FGF23, and to discuss the role of these mechanisms in physiology and pathophysiology.

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Conditional Deletion of Fgfr1 in the Proximal and Distal Tubule Identifies Distinct Roles in Phosphate and Calcium Transport

Cited by 61 publications

References 50 publications

FGF23-Klotho signaling axis in the kidney

FGF23-Klotho signaling axis in the kidney

Mechanisms and Regulation of Intestinal Phosphate Absorption

FGF23 and Vitamin D Metabolism

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