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ABSTRACT: Type IIa sodium-dependent phosphate transporter (NaPi-IIa) is responsible for renal phosphate reabsorption and maintenance of systemic phosphate homeostasis in mammals. Macromolecular complex formation of NaPi-IIa with sodium-proton exchanger related factor-1 (NHERF-1) and ezrin is important for apical membrane localization in the proximal tubular cells. Here, we investigated the interactions of the ezrin phosphomimetic mutation of serine to aspartic acid at 249 with NHERF-1 and the inhibition of apical membrane localization of NaPi-IIa. In vitro phosphorylation analysis revealed that serine 249 of human ezrin serves as a phosphorylation site for protein kinase A. The N-terminal half of ezrin had a dominant negative effect on the phosphate transport activity and inhibited the apical localization of NaPi-IIa in renal proximal tubular cells. We found that the phosphomimetic S249D mutant interfered with the inhibitory effects of the dominant negative mutant on the transport and localization of NaPi-IIa. The S249D mutant also inhibited the interaction with NHERF-1. Therefore, serine 249 of ezrin can play important roles in the regulation of the complex formation and membrane localization of NaPi-IIa. J. Med. Invest. 60: 27-34, February, 2013.
The Journal of Medical Investigation 01/2013; 60(1-2):27-34.
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Tan Vu Van,
Eriko Watari,
Yutaka Taketani,
Tomoyo Kitamura,
Asuka Shiota,
Terumi Tanaka, Ayako Tanimura,
Nagakatsu Harada,
Yutaka Nakaya,
Hironori Yamamoto,
Ken-Ichi Miyamoto,
Eiji Takeda
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ABSTRACT: Hyperphosphatemia causes endothelial dysfunction as well as vascular calcification. Management of serum phosphate level by dietary phosphate restriction or phosphate binders is considered to be beneficial to prevent chronic kidney disease patients from cardiovascular disease, but it has been unclear whether keeping lower serum phosphate level can ameliorate endothelial dysfunction. In this study we investigated whether low-phosphate diet can ameliorate endothelial dysfunction in adenine-induced kidney disease rats, one of useful animal model of chronic kidney disease. Administration of 0.75% adenine-containing diet for 21 days induced renal failure with hyperphosphatemia, and impaired acetylcholine-dependent vasodilation of thoracic aortic ring in rats. Then adenine-induced kidney disease rats were treated with either control diet (1% phosphate) or low-phosphate diet (0.2% phosphate) for 16 days. Low-phosphate diet ameliorated not only hyperphosphatemia but also the impaired vasodilation of aorta. In addition, the activatory phosphorylation of endothelial nitric oxide synthase at serine 1177 and Akt at serine 473 in the aorta were inhibited by in adenine-induced kidney disease rats. The inhibited phosphorylations were improved by the low-phosphate diet treatment. Thus, dietary phosphate restriction can improve aortic endothelial dysfunction in chronic kidney disease with hyperphosphatemia by increase in the activatory phosphorylations of endothelial nitric oxide synthase and Akt.
Journal of Clinical Biochemistry and Nutrition 07/2012; 51(1):27-32. · 1.98 Impact Factor
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Ayako Tanimura,
Fumiyo Yamada,
Akihito Saito,
Mikiko Ito,
Toru Kimura,
Naohiko Anzai,
Daisuke Horie,
Hironori Yamamoto,
Ken-ichi Miyamoto,
Yutaka Taketani,
Eiji Takeda
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ABSTRACT: Type IIa sodium-dependent phosphate transporter (NaPi-IIa) can be localized in the apical plasma membrane of renal proximal tubule to carry out a rate-limiting step of phosphate reabsorption. For the apical localization, NaPi-IIa is required to form a macromolecular complex with some adaptor proteins such as Na(+)/H(+) exchanger regulatory factor 1 (NHERF-1) and ezrin. However, the detail of macromolecular complex containing NaPi-IIa in the apical membrane of the renal proximal tubular cells has not been clarified. In this study, we identified at least four different complexes (220, 480, 920, 1,100 kDa) containing NaPi-IIa by using blue-native polyacrylamide gel electrophoresis. Interestingly, LC-MS/MS analysis and immunoprecipitation analysis reveal that megalin is a component of larger complexes (920 and 1,100 kDa). In addition, NaPi-IIa can be heterogeneously co-localized with ezrin and megalin on the apical membrane of renal proximal tubuler cells by fluorescence microscopy analysis. These results suggest that NaPi-IIa can form some different complexes on the apical plasma membrane of renal proximal tubular cells.
The Journal of Medical Investigation 02/2011; 58(1-2):140-7.
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Takashi Uebanso,
Yutaka Taketani,
Hironori Yamamoto,
Kikuko Amo,
Hirokazu Ominami,
Hidekazu Arai,
Yuichiro Takei,
Masashi Masuda, Ayako Tanimura,
Nagakatsu Harada,
Hisami Yamanaka-Okumura,
Eiji Takeda
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ABSTRACT: Fibroblast growth factor 21 (FGF21) has recently emerged as a metabolic hormone involved in regulating glucose and lipid metabolism in mouse, but the regulatory mechanisms and actions of FGF21 in humans remain unclear. Here we have investigated the regulatory mechanisms of the human FGF21 gene at the transcriptional level. A deletion study of the human FGF21 promoter (-1672 to +230 bp) revealed two fasting signals, including peroxisome proliferator-activated receptor α (PPARα) and glucagon signals, that independently induced human FGF21 gene transcription in mouse primary hepatocytes. In addition, two feeding signals, glucose and xylitol, also dose-dependently induced human FGF21 gene transcription and mRNA expression in both human HepG2 cells and mouse primary hepatocytes. FGF21 protein expression and secretion were also induced by high glucose stimulation. The human FGF21 promoter (-1672 to +230 bp) was found to have a carbohydrate-responsive element at -380 to -366 bp, which is distinct from the PPAR response element (PPRE). Knock-down of the carbohydrate response element binding protein by RNAi diminished glucose-induced human FGF21 transcription. Moreover, we found that a region from -555 to -443 bp of the human FGF21 promoter region exerts an important role in the activation of basic transcription. In conclusion, human FGF21 gene expression is paradoxically and independently regulated by both fasting and feeding signals. These regulatory mechanisms suggest that human FGF21 is increased with nutritional crisis, including starvation and overfeeding.
PLoS ONE 01/2011; 6(8):e22976. · 4.09 Impact Factor
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Kunitaka Nashiki,
Yutaka Taketani,
Emi Shuto,
Rieko Tanaka, Ayako Tanimura,
Naoki Sawada,
Tadatoshi Sato,
Yuichiro Takei,
Hidekazu Arai,
Hironori Yamamoto,
Nagakatsu Harada,
Eiji Takeda
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ABSTRACT: Oxidative stress has emerged as an important pathogenic factor in the development of long-term complications, such as hypertension, atherosclerosis, nephropathy, and cancer. Taking many antioxidants from natural food may be effective to prevent us from those diseases. We have attempted to evaluate the effect of improvement by dietary antioxidants on the endothelial dysfunction induced by hyperglycemia. Fluorescence indicators for reactive oxygen species and nitric oxide were employed to the evaluation. The combination of those fluorescence indicators could be powerful tool to evaluate the effect of anti-stress nutrients on both oxidative stress and endothelial dysfunction.
The Journal of Medical Investigation 12/2005; 52 Suppl:295-6.
