Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter

Segawa, Hiroko; Kawakami, Eri; Kaneko, Ichiro; Kuwahata, Masashi; Ito, Mikiko; Kusano, Koji; Saitô, Hitoshi; Fukushima, Naoshi; Miyamoto, Ken‐ichi

doi:10.1007/s00424-003-1084-1

Cited by 135 publications

(125 citation statements)

References 24 publications

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“…We previously showed that mutant FGF23 inhibited Na/Pi cotransport activity, the expression of NaPi2a and NaPi2c mRNA and protein in renal brush border membrane vesicles (17,20). In the present study, the hypophosphatemia observed in the mutant FGF23-treated uremic rats might be mainly due to the inhibition of the renal Na/Pi cotransporter.…”

Section: Discussionsupporting

confidence: 48%

Mutant FGF23 Prevents the Progression of Chronic Kidney Disease but Aggravates Renal Osteodystrophy in Uremic Rats

Kusano

Saitô

Segawa

et al. 2009

J Nutr Sci Vitaminol

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Summary Phosphorus is one of the important factors that accelerate the progression of chronic kidney disease. Phosphorus restriction or phosphate binders have been reported to have the ability to prevent the progression of chronic kidney disease. FGF23 is a circulating factor that regulates renal phosphorus reabsorption and 1 ␣ -hydroxylase activity. We focused on the phosphaturic activity of FGF23 and investigated whether a pharmacological dose of FGF23 is beneficial to the progression of renal insufficiency in uremic rats. To this end, we administered one of the mutant FGF23 expression plasmids into irreversible Thy1 rats. Chronic renal failure rats were established by intravenous injection of anti-rat CD90 (Thy1.1) monoclonal antibody to unilaterally nephrectomized Wistar rats. The rats were then intravenously injected every 2 wk with a naked DNA solution containing 10 g of MOCK vector or a mutant FGF23 expression plasmid for 13 wk. Renal function was assessed biochemically and histopathologically. Mutant FGF23 significantly decreased serum creatinine and serum urea nitrogen. The marked glomerular sclerosis observed in uremic rats receiving the MOCK vector was ameliorated in rats treated with mutant FGF23. However, mutant FGF23 not only significantly decreased serum 1,25(OH) 2 D and calcium but also aggravated high-turnover renal osteodystrophy from extremely high levels of PTH. These results might be a result of the mechanisms of FGF23 such as phosphaturic activity and lowering the level of 1,25(OH) 2 D. In conclusion, mutant FGF23 prevented the progression of chronic renal failure by regulating serum phosphorus but aggravated renal osteodystrophy from the lowered levels of 1,25(OH) 2 D. Key Words fibroblast growth factor 23, 1,25(OH) 2 D, phosphorus, renal osteodystrophy Disorders of bone and mineral metabolism are found in patients with chronic kidney disease (CKD) and are associated with pathogenesis of secondary hyperparathyroidism. Recent investigations have demonstrated that these abnormalities are also associated with higher mortality due to cardiovascular disease in patients with end stage renal disease ( 1 , 2 ). In patients with CKD who are not yet on dialysis, phosphorus restriction may help to protect the residual renal function ( 3 ). Previous studies using animal models showed the importance of phosphorus regulation. In the chronic renal failure models, a low phosphate diet led to the prevention of the progression of renal failure independent of protein and calorie intake ( 4 ). Furthermore, phosphate binders are reported to prevent the progression of renal insufficiency ( 5 -7 ).Fibroblast growth factor 23 (FGF23) is a novel, secreted protein that consists of 251 amino acids and shares the sequence homology of the fibroblast growth factor family ( 8 ). FGF23 is predominantly expressed in osteocytes but is also expressed in thymus, lymph nodes, and brain ( 9 , 10 ). Transgenic mice that overexpress FGF23 exhibit decreased urinary phosphate reabsorption, hypophosphatemia, low serum 1,25(OH) 2 D ...

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Section: Discussionsupporting

confidence: 48%

Mutant FGF23 Prevents the Progression of Chronic Kidney Disease but Aggravates Renal Osteodystrophy in Uremic Rats

Kusano

Saitô

Segawa

et al. 2009

J Nutr Sci Vitaminol

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“…In addition, fibroblast growth factor 23, a novel phosphaturic factor, acts to decrease type IIc transporter protein and mRNA levels in vivo (8,25). However, other hormonal regulatory mechanisms of the type IIc Na-P i cotransporter remain unknown.…”

Section: Additional Biochemical Findings In Npt2amentioning

confidence: 99%

“…PTH inhibits the expression of the type IIa transporter through the activation of several signal transduction pathways (1,24,25,34). With respect to the distribution of PTH receptor in the renal proximal tubules, hormone binding has been reported in basolateral and in apical membrane preparations (10,18).…”

Section: Additional Biochemical Findings In Npt2amentioning

confidence: 99%

Parathyroid hormone-dependent endocytosis of renal type IIc Na-P_icotransporter

Segawa¹,

Yamanaka²,

Onitsuka³

et al. 2007

American Journal of Physiology-Renal Physiology

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128

105

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Hereditary hypophosphatemic rickets with hypercalciuria results from mutations of the renal type IIc Na-Pi cotransporter gene, suggesting that the type IIc transporter plays a prominent role in renal phosphate handling. The goal of the present study was to investigate the regulation of the type IIc Na-Pi cotransporter by parathyroid hormone (PTH). Type IIc Na-Pi cotransporter levels were markedly increased in thyroparathyroidectomized (TPTX) rats. Four hours after administration of PTH, type IIc transporter protein levels were markedly decreased in the apical membrane fraction but recovered to baseline levels at 24 h. Immunohistochemical analyses demonstrated the presence of the type IIc transporter in the apical membrane and subapical compartments in the proximal tubular cells in TPTX animals. After administration of PTH, the intensity of immunoreactive signals in apical and subapical type IIc transporter decreased in the renal proximal tubular cells in TPTX rats. Colchicine completely blocked the internalization of the type IIc transporter. In addition, leupeptin prevented the PTH-mediated degradation of the type IIa transporter in lysosomes but had no effect on PTH-mediated degradation of the lysosomal type IIc transporter. In PTH-treated TPTX rats, the internalization of the type IIc transporter occurred after administration of PTH(1-34) (PKA and PKC activator) or PTH(3-34) (PKC activator). Thus the present study demonstrated that PTH is a major hormonal regulator of the type IIc Na-Pi cotransporter in renal proximal tubules. phosphate transporter; proximal tubule; regulation INORGANIC PHOSPHATE (P i ) reabsorption in the renal proximal tubule is required for body P i homeostasis, and Na ϩ -dependent P i (Na-P i ) transporters in the brush-border membrane (BBM) of proximal tubular cells mediate the rate-limiting step in the overall P i -reabsorptive process (17, 19 -21). The type IIa and type IIc Na-P i cotransporters are expressed in the apical membrane of proximal tubular cells and mediate Na-P i cotransport, and the extent of P i reabsorption in the proximal tubules is determined largely by the abundance of the type IIa Na-P i cotransporter (17, 19 -21, 28). Indeed, Na-P i cotransporter type IIa-deficient mice (Npt2a Ϫ/Ϫ mice) exhibit increased urinary P i excretion, hypophosphatemia, and an appropriate adaptive increase in the circulating concentration of 1,25(OH) 2 D 3 (2, 28). Additional biochemical findings in Npt2aϪ/Ϫ mice include hypercalcemia, hypercalciuria, decreased serum parathyroid hormone (PTH) levels, and elevated serum alkaline phosphatase activity (2, 28). These biochemical features are typical of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a Mendelian disorder of renal P i reabsorption (6, 30). However, in contrast to patients with HHRH, Npt2a Ϫ/Ϫ mice do not exhibit rickets and osteomalacia (2, 7, 28), and linkage analyses indicated that the Npt2a gene is not a candidate for HHRH patients (9, 33).More recently, two groups demonstrated that HHRH results f...

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“…El FGF suprime la expresión del cotransportador de sodio y fosfato NPT2a y NPT2c incrementando así la excreción urinaria de fosfato a nivel de túbulo contorneado proximal (18,19) .…”

Section: Factor De Crecimiento De Fibroblastos 23 (Fgf-23)unclassified

Metabolismo mineral óseo en pacientes con enfermedad renal crónica: revisión sobre su fisiopatología y morbimortalidad

Bernuy

Gonzáles

2015

Rev Peru Med Exp Salud Publica

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RESUMENLa enfermedad mineral ósea (EMO) es un término amplio que incluye a las alteraciones séricas del calcio, fósforo, vitamina D, paratohormona, anormalidades en el crecimiento, mineralización ósea y/o a las calcificaciones extraesqueléticas que acompañan al paciente con enfermedad renal crónica (ERC). Está presente en casi la totalidad de pacientes en diálisis y con el trasplante renal puede no siempre mejorar. Se han identificado nuevos factores y hormonas; como klotho y factor de crecimiento de fibroblastos-23 (FGF-23) que interactúan con la vitamina D y con la paratohormona en el manejo renal del calcio y fósforo. Ciertos reportes indican que son marcadores precoces del desarrollo de EMO, incluso cuando la función renal está levemente disminuida y los niveles de paratohormona son normales. La EMO ha sido asociada con mayor mortalidad, principalmente por su vinculación con la calcificación vascular. Este proceso conlleva a un incremento de eventos cardiovasculares que constituyen la principal causa de morbimortalidad en pacientes con ERC, sobre todo aquellos que se encuentran en diálisis, independientemente de la modalidad que los pacientes sigan. La forma de presentación de la EMO puede ser de alto o bajo recambio. Aunque no está completamente definido qué es lo que determina que se exprese una en particular, se ha encontrado que la enfermedad de bajo recambio se relaciona con malnutrición, uso inadecuado de calcitriol y diálisis ineficiente. El conocimiento de la EMO es relevante por su asociación con las complicaciones mencionadas y porque constituye un parámetro para evaluar la terapia instalada. Palabras clave: Hormona paratiroidea; Deficiencia de vitamina B; Enfermedad renal crónica; Trastornos del metabolismo del calcio (fuente: DeCS BIREME). BONE MINERAL METABOLISM IN PATIENTS WITH CHRONIC KIDNEY DISEASE: REVIEW OF ITS PATHOPHYSIOLOGY AND MORBIMORTALITY ABSTRACTMineral Bone Disorder (MBD) is a broad term that includes abnormal serum calcium, phosphorus, vitamin D, parathyroid hormone, growth abnormalities, bone mineralization and/or extraskeletal calcifications in patients with chronic kidney disease (CKD ). It is present in almost all patients on dialysis and may not always improve with a kidney transplant. New factors and hormones have been identified, such as Klotho and fibroblast growth factor-23 (FGF-23) that interact with vitamin D and the parathyroid hormone in the renal management of calcium and phosphorus. Some reports indicate that they are early markers of the development of MBD, even when kidney function is slightly decreased and parathyroid hormone levels are normal. MBD has been associated with higher mortality, mainly because of its link with vascular calcification. This process leads to an increase in cardiovascular events which are the leading cause of morbidity and mortality in CKD patients, especially those who are on dialysis, regardless of the modality that the patients follow. The presentation of the BMD can be of high or low turnover. Although it is not completely defined wha...

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Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter

Cited by 135 publications

References 24 publications

Mutant FGF23 Prevents the Progression of Chronic Kidney Disease but Aggravates Renal Osteodystrophy in Uremic Rats

Mutant FGF23 Prevents the Progression of Chronic Kidney Disease but Aggravates Renal Osteodystrophy in Uremic Rats

Parathyroid hormone-dependent endocytosis of renal type IIc Na-P_icotransporter

Metabolismo mineral óseo en pacientes con enfermedad renal crónica: revisión sobre su fisiopatología y morbimortalidad

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Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter

Cited by 135 publications

References 24 publications

Mutant FGF23 Prevents the Progression of Chronic Kidney Disease but Aggravates Renal Osteodystrophy in Uremic Rats

Mutant FGF23 Prevents the Progression of Chronic Kidney Disease but Aggravates Renal Osteodystrophy in Uremic Rats

Parathyroid hormone-dependent endocytosis of renal type IIc Na-Picotransporter

Metabolismo mineral óseo en pacientes con enfermedad renal crónica: revisión sobre su fisiopatología y morbimortalidad

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Parathyroid hormone-dependent endocytosis of renal type IIc Na-P_icotransporter