scholarly journals Pleiotropic Actions of FGF23

2017 ◽  
Vol 45 (7) ◽  
pp. 904-910 ◽  
Author(s):  
Reinhold G. Erben
Keyword(s):  
Vitamin D ◽  
Fibroblast Growth Factor 23 ◽  
Renal Tubules ◽  
Hormone Production ◽  
Membrane Expression ◽  
Fgf Receptor ◽  
Local Inhibition ◽  
Organ Systems ◽  
Key Enzyme ◽  
Renal Tubular

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone, mainly produced by osteoblasts and osteocytes in response to increased extracellular phosphate and circulating vitamin D hormone. Endocrine FGF23 signaling requires co-expression of the ubiquitously expressed FGF receptor 1 (FGFR1) and the co-receptor α-Klotho (Klotho). In proximal renal tubules, FGF23 suppresses the membrane expression of the sodium–phosphate cotransporters Npt2a and Npt2c which mediate urinary reabsorption of filtered phosphate. In addition, FGF23 suppresses proximal tubular expression of 1α-hydroxylase, the key enzyme responsible for vitamin D hormone production. In distal renal tubules, FGF23 signaling activates with-no-lysine kinase 4, leading to increased renal tubular reabsorption of calcium and sodium. Therefore, FGF23 is not only a phosphaturic but also a calcium- and sodium-conserving hormone, a finding that may have important implications for the pathophysiology of chronic kidney disease. Besides these endocrine, Klotho-dependent functions of FGF23, FGF23 is also an auto-/paracrine suppressor of tissue-nonspecific alkaline phosphatase transcription via Klotho-independent FGFR3 signaling, leading to local inhibition of mineralization through accumulation of pyrophosphate. In addition, FGF23 may target the heart via an FGFR4-mediated Klotho-independent signaling cascade. Taken together, there is emerging evidence that FGF23 is a pleiotropic hormone, linking bone with several other organ systems.

RENAL TUBULAR DYSFUNCTION COMPLICATING THE NEPHROTIC SYNDROME

PEDIATRICS ◽  
1960 ◽  
Vol 26 (1) ◽  
pp. 75-85
Author(s):  
Gunnar B. Stickler ◽  
Alvin B. Hayles ◽  
Marschelle H. Power ◽  
John A. Ulrich
Keyword(s):  
Vitamin D ◽  
Nephrotic Syndrome ◽  
Metabolic Acidosis ◽  
Renal Insufficiency ◽  
Tubular Dysfunction ◽  
Renal Tubular Dysfunction ◽  
Renal Tubules ◽  
Renal Tubular ◽  
Amino Aciduria ◽  
Unusual Type

Observations on two girls in whom an unusual type of chronic renal insufficiency developed many months after the onset of nephrotic syndrome are reported. Each patient became free of edema in spite of persistent massive proteinuria. Growth was retarded and rickets and attacks of tetany developed. The chemical disturbances of the blood were characterized by hypocalcemia, hypokalemia, azotemia and metabolic acidosis. Hyposthenuria, proteinuria, amino-aciduria, and minimal erythrocyturia, cylindruria and glycosuria were present. Healing of the rickets and cessation of attacks of tetany followed the administration of vitamin D and calcium salts. Prednisone was administered to one patient and thereafter proteinuria decreased and renal tubular function improved. Both girls are relatively asymptomatic 11 and 9 years after the onset of nephrotic syndrome, although they are rather small and still have evidence of renal disease. It is possible that cells of the renal tubules have been damaged as a result of prolonged massive proteinuria.

Familial hypocalciuric hypercalcaemia: observations on vitamin D metabolism and parathyroid function

1983 ◽  
Vol 104 (2) ◽  
pp. 210-215 ◽  
Author(s):  
M. Davies ◽  
P. H. Adams ◽  
J. L. Berry ◽  
G. A. Lumb ◽  
P. S. Klimiuk ◽  
...  
Keyword(s):  
Vitamin D ◽  
Serum Concentration ◽  
Primary Hyperparathyroidism ◽  
Calcium Excretion ◽  
Renal Tubules ◽  
Vitamin D Metabolites ◽  
Vitamin D Metabolism ◽  
Hydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Renal Tubular

Abstract. Serum vitamin D metabolites, the renal tubular maximum reabsorptive rate for phosphate (TMP/GFR) nephrogenic cyclic AMP (NcAMPI, and CaE (urinary calcium excretion per litre of glomerular filtrate) were measured in 14 adults with familial hypocalciuric hypercalcaemia (FHH). The findings were compared with analyses in 14 patients with surgically proven primary hyperparathyroidism matched for serum calcium, creatinine clearance and vitamin D status (assessed by serum concentrations of 25 hydroxyvitamin D). Vitamin D metabolites were also measured in 16 normocalcaemic relatives of patients with FHH. The serum concentration of 24, 25 dihydroxycholecalciferol was appropriate for the prevailing 25 hydroxyvitamin D and no difference was found between groups. The serum concentration of 1, 25 dihydroxycholecalciferol was significantly greater in primary hyperparathyroidism (P < 0.0005) compared with patients with FHH and their normocalcaemic relatives. TMP/GFR was reduced in both primary hyperparathyroidism (0.53 ± 0.12 mmol/l GF, mean ± sem) and FHH (0.86 ±0.14 mmol/l GF). Patients with primary hyperparathyroidism showed an increase in NcAMP output in the urine (38.5 ± 16 mmol/l GF) which was significantly greater (P < 0.0001) than the normal NcAMP (13.5 ± 9.2 nmol/l GF) found in FHH. CaE was low in FHH indicating increased renal tubular reabsorption of calcium. It is concluded that there is no abnormality of vitamin D metabolism in FHH comparable with the changes observed in primary hyperparathyroidism. It is suggested that the biochemical abnormalities in FHH cannot be explained solely upon an increased sensitivity of the renal tubules to the effects of endogenous parathyroid hormone.

scholarly journals Two Cases of Hypophosphatemia with Increased Renal Phosphate Excretion in Legionella Pneumonia

2016 ◽  
Vol 6 (1) ◽  
pp. 40-45 ◽  
Author(s):  
Shuhei Watanabe ◽  
Keiji Kono ◽  
Hideki Fujii ◽  
Kentaro Nakai ◽  
Shunsuke Goto ◽  
...  
Keyword(s):  
Vitamin D ◽  
Fibroblast Growth Factor 23 ◽  
Tubular Dysfunction ◽  
Renal Tubular Dysfunction ◽  
Fibroblast Growth ◽  
Phosphate Excretion ◽  
Legionella Pneumonia ◽  
Vitamin D Levels ◽  
Renal Tubular ◽  
Renal Phosphate Excretion

We encountered 2 cases of hypophosphatemia due to Legionella pneumonia. Both cases showed increased urinary phosphate excretion and renal tubular dysfunction, which ameliorated with recovery from Legionella pneumonia. Serum fibroblast growth factor-23 level was suppressed, whereas serum 1,25(OH)2 vitamin D and parathyroid hormone levels were normal. Delayed elevation of serum 1,25(OH)2 vitamin D levels was observed with improvement in renal tubular function. These findings suggested hypophosphatemia might be mediated by renal tubular dysfunction.

scholarly journals CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease

2010 ◽  
Vol 298 (2) ◽  
pp. F365-F380 ◽  
Author(s):  
Anita A. C. Reed ◽  
Nellie Y. Loh ◽  
Sara Terryn ◽  
Jonathan D. Lippiat ◽  
Chris Partridge ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Endocytic Pathway ◽  
Cell Surface Expression ◽  
Renal Tubules ◽  
Membrane Expression ◽  
Dent’S Disease ◽  
Dent's Disease ◽  
Plasma Membrane Expression ◽  
Renal Tubular Disorder ◽  
Renal Tubular

Renal tubular reabsorption is important for extracellular fluid homeostasis and much of this occurs via the receptor-mediated endocytic pathway. This pathway is disrupted in Dent’s disease, an X-linked renal tubular disorder that is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. Dent's disease is due to mutations of CLC-5, a chloride/proton antiporter, expressed in endosomes and apical membranes of renal tubules. Loss of CLC-5 function alters receptor-mediated endocytosis and trafficking of megalin and cubilin, although the underlying mechanisms remain to be elucidated. Here, we report that CLC-5 interacts with kinesin family member 3B (KIF3B), a heterotrimeric motor protein that facilitates fast anterograde translocation of membranous organelles. Using yeast two-hybrid, glutathione- S-transferase pull-down and coimmunoprecipitation assays, the COOH terminus of CLC-5 and the coiled-coil and globular domains of KIF3B were shown to interact. This was confirmed in vivo by endogenous coimmunoprecipitation of CLC-5 and KIF3B and codistribution with endosomal markers in mouse kidney fractions. Confocal live cell imaging in kidney cells further demonstrated association of CLC-5 and KIF3B, and transport of CLC-5-containing vesicles along KIF3B microtubules. KIF3B overexpression and underexpression, using siRNA, had reciprocal effects on whole cell chloride current amplitudes, CLC-5 cell surface expression, and endocytosis of albumin and transferrin. Clcn5Y/− mouse kidneys and isolated proximal tubular polarized cells showed increased KIF3B expression, whose effects on albumin endocytosis were dependent on CLC-5 expression. Thus, the CLC-5 and KIF3B interaction is important for CLC-5 plasma membrane expression and for facilitating endocytosis and microtubular transport in the kidney.

scholarly journals Soluble Klotho causes hypomineralization in Klotho-deficient mice

2018 ◽  
Vol 237 (3) ◽  
pp. 285-300 ◽  
Author(s):  
Tomoko Minamizaki ◽  
Yukiko Konishi ◽  
Kaoru Sakurai ◽  
Hirotaka Yoshioka ◽  
Jane E Aubin ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Type I ◽  
Fgf Receptor ◽  
Hypervitaminosis D ◽  
Downstream Effector ◽  
Organ Systems ◽  
Deficient Mice

The type I transmembrane protein αKlotho (Klotho) serves as a coreceptor for the phosphaturic hormone fibroblast growth factor 23 (FGF23) in kidney, while a truncated form of Klotho (soluble Klotho, sKL) is thought to exhibit multiple activities, including acting as a hormone, but whose mode(s) of action in different organ systems remains to be fully elucidated. FGF23 is expressed primarily in osteoblasts/osteocytes and aberrantly high levels in the circulation acting via signaling through an FGF receptor (FGFR)-Klotho coreceptor complex cause renal phosphate wasting and osteomalacia. We assessed the effects of exogenously added sKL on osteoblasts and bone using Klotho-deficient (kl/kl) mice and cell and organ cultures. sKL induced FGF23 signaling in bone and exacerbated the hypomineralization without exacerbating the hyperphosphatemia, hypercalcemia and hypervitaminosis D in kl/kl mice. The same effects were seen in rodent bone models in vitro, in which we also detected formation of a sKL complex with FGF23-FGFR and decreased Phex (gene responsible for X-linked hypophosphatemic rickets (XLH)/osteomalacia) expression. Further, sKL-FGF23-dependent hypomineralization in vitro was rescued by soluble PHEX. These data suggest that exogenously added sKL directly participates in FGF23 signaling in bone and that PHEX is a downstream effector of the sKL-FGF23-FGFR axis in bone.

scholarly journals A case of X-linked hypophosphatemic rickets: complications and the therapeutic use of cinacalcet

2008 ◽  
Vol 159 (suppl_1) ◽  
pp. S101-S105 ◽  
Author(s):  
Helge Ræder ◽  
Nick Shaw ◽  
Coen Netelenbos ◽  
Robert Bjerknes
Keyword(s):  
Vitamin D ◽  
Sodium Phosphate ◽  
Fibroblast Growth Factor 23 ◽  
Normal Growth ◽  
Current Treatment ◽  
Phosphate Transporter ◽  
Hypophosphatemic Rickets ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Bone Deformities

In hypophosphatemic rickets, there are both inherited and acquired forms, where X-linked dominant hypophosphatemic rickets (XLH) is the most prevalent genetic form and caused by mutations in the phosphate-regulating endopeptidase (PHEX) gene. XLH is associated with growth retardation and bone deformities. The renal tubular cells have an important role in calcium and phosphate metabolism, where the 1α-hydroxylase enzyme metabolizes the conversion of 25 (OH)-vitamin D to potent 1,25 (OH)2-vitamin D, whereas the sodium–phosphate transporter controls tubular phosphate reabsorption. The pathophysiological defect in XLH is speculated to cause an increase in a circulating phosphate regulating hormone termed phosphatonin (fibroblast growth factor 23 is the primary phosphatonin candidate), which leads to inhibition of 1α-hydroxylase, and simultaneously to inhibition of the sodium–phosphate transporter domain NPT2c leading to parathyroid hormone-independent phosphaturia. Hence, current treatment of XLH is 1,25 (OH)2-vitamin D or the vitamin D analog alfacalcidol and elementary phosphorus. Unfortunately, patients with XLH may develop nephrocalcinosis, secondary or tertiary hyperparathyroidism, and in some situations also hypertension and cardiovascular abnormalities. We describe a patient with XLH caused by a novel missense mutation in the PHEX gene, who on treatment with alfacalcidol and oral phosphate had normal growth and minimal bone deformities, but who subsequently developed moderate nephrocalcinosis, significant hyperparathyroidism, hypercalcemia, renal failure, and hypertension. We also report the use of the calcimimetic drug cinacalcet in the successful treatment of hypercalcemia and hyperparathyroidism.

scholarly journals Permissive effect of GSK3β on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Bohan Chen ◽  
Pei Wang ◽  
Xianhui Liang ◽  
Chunming Jiang ◽  
Yan Ge ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Binding Protein ◽  
Renal Tubules ◽  
Genetic Ablation ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Renal Fibrogenesis ◽  
Tgf Β1

AbstractRenal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3β overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-β1 treatment augmented GSK3β expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3β inhibitors or by ectopic expression of a dominant-negative mutant of GSK3β but reinforced in cells expressing the constitutively active mutant of GSK3β. Mechanistically, GSK3β suppressed, whereas inhibiting GSK3β facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-β1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3β in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3β is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

Fibroblast growth factor 23 and its role in phosphate homeostasis in growing children compared to adults

2020 ◽  
Vol 33 (8) ◽  
pp. 1065-1071
Author(s):  
Marjan Jeddi ◽  
Maryam Heidari ◽  
Neda Hatami ◽  
Gholam Hossein Ranjbar Omrani
Keyword(s):  
Vitamin D ◽  
Alkaline Phosphatase ◽  
Fibroblast Growth Factor 23 ◽  
Fractional Excretion ◽  
Cross Sectional Study ◽  
Fibroblast Growth ◽  
Sectional Study ◽  
Phosphate Homeostasis ◽  
Cross Sectional ◽  
Fractional Excretion Of Phosphate

AbstractObjectivesPhosphate is essential for skeletal mineralization, which is regulated by parathyroid hormone, calcitriol and fibroblast growth factor 23 (FGF23). Serum phosphate is physiologically higher in younger children, but factors that contribute to this physiological state are poorly understood. This study aimed to evaluate phosphate and its regulators in children compared with adults.Materials and methodsThe participants were children aged 3–11 years and adults older than 20 years of age. Biochemical parameters including calcium, phosphorus, alkaline phosphatase, FGF23, and vitamin D were measured. Fractional excretion of phosphate was calculated, using serum and urine phosphate and creatinine.ResultsThis cross-sectional study was conducted on 45 children (mean age: 9.0 ± 2.1) and 44 adults (mean age: 38.9 ± 11.1). The children had higher serum calcium, phosphate, alkaline phosphatase, and FGF23 (p < 0.001), but fractional excretion of phosphate was greater in adults (14.1 ± 5.7, 11.4 ± 4.4, p = 0.019, 95% confidence interval [CI]: −0.7 to −0.2). Of all individuals, 61.8% had vitamin D deficiency. By multiple regression analysis, entering age, calcium, phosphate, and vitamin D level, the only independent predictor of FGF23 was 1, 25 dihydroxy-vitamin D3 (β: 0.78, p < 0.001, 95% CI: 0.5–1.1, R2: 0.59 for children, and β: 0.59, p < 0.001, 95% CI: 0.5–1.4, R2: 0.45 for adults).ConclusionAs far as we know, there is little information regarding the role of FGF23 in physiologic state. In this cross-sectional study no association was found between FGF23 and urinary phosphate excretion in growing children. Further studies with more detail are essential to evaluate phosphate homeostasis during childhood.

scholarly journals The Metabolic Bone Disease X-linked Hypophosphatemia: Case Presentation, Pathophysiology and Pharmacology

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 563
Author(s):  
Jon Vincze ◽  
Brian W. Skinner ◽  
Katherine A. Tucker ◽  
Kory A. Conaway ◽  
Jonathan W. Lowery ◽  
...  
Keyword(s):  
Vitamin D ◽  
Biological Effects ◽  
Fibroblast Growth Factor 23 ◽  
Elevated Serum ◽  
Fractional Excretion ◽  
The United States ◽  
Vitamin D Supplementation ◽  
Loss Of Function ◽  
Case Presentation ◽  
Serum Inorganic Phosphate

The authors present a stereotypical case presentation of X-linked hypophosphatemia (XLH) and provide a review of the pathophysiology and related pharmacology of this condition, primarily focusing on the FDA-approved medication burosumab. XLH is a renal phosphate wasting disorder caused by loss of function mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). Typical biochemical findings include elevated serum levels of bioactive/intact fibroblast growth factor 23 (FGF23) which lead to (i) low serum phosphate levels, (ii) increased fractional excretion of phosphate, and (iii) inappropriately low or normal 1,25-dihydroxyvitamin D (1,25-vitD). XLH is the most common form of heritable rickets and short stature in patients with XLH is due to chronic hypophosphatemia. Additionally, patients with XLH experience joint pain and osteoarthritis from skeletal deformities, fractures, enthesopathy, spinal stenosis, and hearing loss. Historically, treatment for XLH was limited to oral phosphate supplementation, active vitamin D supplementation, and surgical intervention for cases of severe bowed legs. In 2018, the United States Food and Drug Administration (FDA) approved burosumab for the treatment of XLH and this medication has demonstrated substantial benefit compared with conventional therapy. Burosumab binds circulating intact FGF23 and blocks its biological effects in target tissues, resulting in increased serum inorganic phosphate (Pi) concentrations and increased conversion of inactive vitamin D to active 1,25-vitD.

scholarly journals Renal Dnase1 expression is regulated by FGF23 but loss of Dnase1 does not alter renal phosphate handling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniela Egli-Spichtig ◽  
Martin Y. H. Zhang ◽  
Alfred Li ◽  
Eva Maria Pastor Arroyo ◽  
Nati Hernando ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Actin Polymerization ◽  
Fibroblast Growth Factor 23 ◽  
Wild Type ◽  
Vitamin D Metabolism ◽  
Endocrine Hormone ◽  
Dnase 1 ◽  
Sodium Dependent ◽  
Renal Tubular ◽  
High Phosphate

AbstractFibroblast growth factor 23 (FGF23) is a bone-derived endocrine hormone that regulates phosphate and vitamin D metabolism. In models of FGF23 excess, renal deoxyribonuclease 1 (Dnase1) mRNA expression is downregulated. Dnase-1 is an endonuclease which binds monomeric actin. We investigated whether FGF23 suppresses renal Dnase-1 expression to facilitate endocytic retrieval of renal sodium dependent phosphate co-transporters (NaPi-IIa/c) from the brush border membrane by promoting actin polymerization. We showed that wild type mice on low phosphate diet and Fgf23−/− mice with hyperphosphatemia have increased renal Dnase1 mRNA expression while in Hyp mice with FGF23 excess and hypophosphatemia, Dnase1 mRNA expression is decreased. Administration of FGF23 in wild type and Fgf23−/− mice lowered Dnase1 expression. Taken together, our data shows that Dnase1 is regulated by FGF23. In 6-week-old Dnase1−/− mice, plasma phosphate and renal NaPi-IIa protein were significantly lower compared to wild-type mice. However, these changes were transient, normalized by 12 weeks of age and had no impact on bone morphology. Adaptation to low and high phosphate diet were similar in Dnase1−/− and Dnase1+/+ mice, and loss of Dnase1 gene expression did not rescue hyperphosphatemia in Fgf23−/− mice. We conclude that Dnase-1 does not mediate FGF23-induced inhibition of renal tubular phosphate reabsorption.

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