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Regulation of α-Klotho Expression by Dietary Phosphate During Growth Periods

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Abstract

Inorganic phosphate (Pi) is an essential nutrient for maintaining various biological functions, particularly during growth periods. Excess intake of dietary Pi increases the secretion of fibroblast growth factor 23 (FGF23) and parathyroid hormone to maintain plasma Pi levels. FGF23 is a potent phosphaturic factor that binds to the α-klotho/FGFR complex in the kidney to promote excretion of Pi into the urine. In addition, excess intake of dietary Pi decreases renal α-klotho expression. Down-regulation or lack of α-klotho induces a premature aging-like phenotype, resulting from hyperphosphatemia, and leading to conditions such as ectopic calcification and osteoporosis. However, it remains unclear what effects dietary Pi has on α-klotho expression at different life stages, especially during growth periods. To investigate this, we used C57BL/6J mice in two life stages during growing period. Weaned (3 weeks old) and periadolescent (7 weeks old) were randomly divided into seven experimental groups and fed with 0.02, 0.3, 0.6, 0.9, 1.2, 1.5, or 1.8% Pi diets for 7 days. As a result, elevated plasma Pi and FGF23 levels and decreased renal α-klotho expression were observed in weaned mice fed with a high Pi diet. In addition, a high Pi diet clearly induced renal calcification in the weaned mice. However, in the periadolescent group, renal calcification was not observed, even in the 1.8% Pi diet group. The present study indicates that a high Pi diet in weaned mice has much greater adverse effects on renal α-klotho expression and pathogenesis of renal calcification compared with periadolescent mice.

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Acknowledgements

We thank Shoko Ikeda, Mari Nakao, Nozomi Yokoyama, Rina Onishi, Kazuki Fujimoto, Natsuki Oka (Department of Clinical Nutrition and Food Management, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan) for technical assistance.

Funding

Funding was provided by Japan Society for the Promotion of Science (Grant No. 16H03046).

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Authors and Affiliations

  1. Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Shiori Fukuda-Tatano, Hironori Yamamoto, Otoki Nakahashi, Ryouhei Yoshikawa, Mayu Hayashi, Maki Kishimoto, Hisami Yamanaka-Okumura, Kohta Ohnishi, Masashi Masuda & Yutaka Taketani

  2. Department of Health and Nutrition, Faculty of Nursing and Nutrition, The University of Shimane, 151 Nishihayashigi, Izumo, Shimane, 693-8550, Japan

    Shiori Fukuda-Tatano

  3. Department of Health and Nutrition, Faculty of Human Life, Jin-ai University, Ohde-cho 3-1-1, Echizen, Fukui, 915-8586, Japan

    Hironori Yamamoto

  4. Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan

    Hironori Yamamoto

  5. Division of Functional Food Chemistry, Institute for Health Science, Tokushima Bunri University, 180 Nishihamahoji, Yamashiro-cho, Tokushima, Tokushima, 770-8514, Japan

    Otoki Nakahashi

  6. Department of Clinical Nutrition and Dietetics, Konan Women’s University, Kobe, 658-0001, Japan

    Yukiko Imi

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  1. Shiori Fukuda-Tatano
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  11. Yutaka Taketani
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Correspondence to Yutaka Taketani.

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Conflict of interest

Shiori Fukuda-Tatano, Hironori Yamamoto, Otoki Nakahashi, Ryouhei Yoshikawa, Mayu Hayashi, Maki Kishimoto, Yukiko Imi, Hisami Yamanaka-Okumura, Kohta Ohnishi, Masashi Masuda, and Yutaka Taketani declare no conflicts of interest.

Human and Animal Rights and Informed Consent

The present study was approved by the Animal Experimentation Committee of Tokushima University and was conducted in accordance with the guidelines for the management and handling of experimental animals.

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Fukuda-Tatano, S., Yamamoto, H., Nakahashi, O. et al. Regulation of α-Klotho Expression by Dietary Phosphate During Growth Periods. Calcif Tissue Int 104, 667–678 (2019). https://doi.org/10.1007/s00223-019-00525-0

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