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1 Department of Molecular Nutrition, Institution of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
2 Tokushima, Japan; Department of Molecular Nutrition, Institution of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
3 Department of Clinical Nutrition, Institution of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
* To whom correspondence should be addressed. E-mail: miyamoto{at}nutr.med.tokushima-u.ac.jp.
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) results from mutations of the renal type IIc Na/Pi cotransporter gene cause, 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 hr. Immunohistochemical analysis demonstrated 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 proximate tubule 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 the treatment of PTH into TPTX rats, the internalization of the type IIc transporter was occurred by administration of 1-34PTH (PKA and PKC activator) or 3-34PTH (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.
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