Parathyroid hormone action on phosphate transporter mRNA and protein in rat renal proximal tubules

Kempson, Stephen A.; Lötscher, Marius; Kaissling, Brigitte; Biber, Jürg; Murer, H; Levi, Moshe

doi:10.1152/ajprenal.1995.268.4.f784

Cited by 123 publications

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“…Type II Na/Pi activity is increased by a low serum P and decreased by parathyroid hormone (PTH) and FGF23 (4 -8). The regulation of type II Na/Pi is at the level of recruitment of new transporters to the apical proximal tubule membrane, the level of synthesis of new transporters and their breakdown (5,9). In addition, there is regulation at the level of type II Na/Pi gene expression, which in vivo is mainly posttranscriptional (10,11).…”

mentioning

confidence: 99%

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Moz¹,

Levi²,

Lavi-Moshayoff³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The sensing and response to extracellular phosphate (Pi) concentration is preserved from prokaryotes to mammals and ensures an adequate supply of Pi in the face of large differences in its availability. In mammals, the kidneys are central to Pi homeostasis. Renal Pi reabsorption is mediated by a Na/Pi co-transporter that is regulated by a renal Pi sensing system and humoral factors. The signal transduction by which Pi regulates type II Na/Pi activity is largely unknown. It is shown that calcineurin inhibitors specifically and dramatically decrease type II Na/Pi gene expression in a proximal tubule cell line and in vivo. Mice with genetic deletion of the calcineurin A␤ gene had a marked decrease in type II Na/Pi mRNA levels and remarkably did not show the expected increase in type II Na/Pi mRNA levels after the challenge of a low-Pi diet. In contrast, the regulation of renal 25(OH)-vitamin D 1␣-hydroxylase gene expression by Pi was intact. This is the first demonstration that calcineurin has a crucial role in the signal transduction pathway regulating renal Pi homeostasis both in vitro and in vivo. These results suggest that the use of calcineurin inhibitors contributes to the renal Pi wasting seen in renal transplant patients.Phosphate (Pi) homeostasis is essential to life and is dependent on active renal reabsorption. In diseases of phosphorus (P) homeostasis, such as X-linked hypophosphatemia or oncogenic osteomalacia, there is a tremendous renal P loss with severe bone disease (1). In contrast, in chronic renal failure, the P retention leads to secondary hyperparathyroidism with disabling bone disease and vascular calcification associated with a high mortality (2). The kidney has an intrinsic P sensing system that regulates the activity of apical brush border membrane type II Na/Pi co-transporters (3). However, it is still not known how the organism senses changes in serum P.There are three mammalian Na/Pi co-transporter families: types I through III. Type II Na/Pi activity is responsible for Ͼ80% of renal P reabsorption and contains three isoforms-IIa through c-of which IIa is the major factor in renal P reabsorption and regulation in adult mice (4). Type II Na/Pi activity is increased by a low serum P and decreased by parathyroid hormone (PTH) and FGF23 (4 -8). The regulation of type II Na/Pi is at the level of recruitment of new transporters to the apical proximal tubule membrane, the level of synthesis of new transporters and their breakdown (5,9). In addition, there is regulation at the level of type II Na/Pi gene expression, which in vivo is mainly posttranscriptional (10,11). In the rat, a cis acting element in the type II Na/Pi co-transporter (Na/Pi-2) mRNA at the junction of the coding region and the 3'-untranslated region (UTR) interacts with trans acting renal cytosolic proteins and determines Na/Pi-2 mRNA stability in response to dietary P restriction (12). An additional level of regulation of Na/Pi-2 is its translational control by a low-P diet (10).The renal type II Na/Pi co-transporte...

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mentioning

confidence: 99%

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Moz¹,

Levi²,

Lavi-Moshayoff³

et al. 2004

Journal of the American Society of Nephrology

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“…In tissue culture experiments we have generated evidence for an involvement of an endocytic step in PTH-action [14]. In immunohistochemical studies we documented that infusion of PTH leads in rat proximal tubules to an immediate removal of apical Na/P r cotransporters and to their appearance in intracellular structures (also in subapical vesicles; Figure 1) [8]. It is the task of future experiments to determine the signalling events linking the PTH-receptor occupancy to withdrawal and inactivation of brush border membrane Na/Pj-Intact Intact + PTH (2 hours) Fig.…”

Section: Physiological Regulationmentioning

confidence: 96%

“…We will only discuss briefly two examples: Parathyroid hormone (PTH), as a known phosphaturic hormone, mediates its inhibitory action on Na/P r cotransport by activating a complex intracellular regulatory machinery; the initial step is interaction with a hormone receptor capable of activating the adenylate cyclase (protein kinase A) and the phospholipase-C (protein kinase C) pathways [12]. The Type II Na/Pjcotransporter is a target for PTH regulation [8]. If the rat II transporter is expressed in oocytes, Na/P,-cotransporter activity is reduced by pharmacological activation of protein kinase C but not of protein kinase A [7].…”

Section: Physiological Regulationmentioning

confidence: 99%

“…As seen in control animals the Type II transporter is located mostly at brush border sites and appears as 'yellow' ('colocalization' of p-actin and transporter). After PTH-treatment the transporter is removed from the brush border structure (red/P-actin) and appears now in intracellular compartments (green; mostly subapical endosomes) [8].…”

Section: Physiological Regulationmentioning

confidence: 99%

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Molecular mechanisms in renal phosphate reabsorption

1995

Nephrology Dialysis Transplantation

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Nephrol Dial Transplant 1995: Editorial Comments of the vascular structure. Binding to adhesion molecules regulates the migration of leukocytes from the blood stream into the vessel wall inflammatory diseases [4]. Adhesion molecules seem also to play a role in the migration of endothelial cells into the vessel wall during angiogenesis, as well as the migration of vascular smooth muscle cells from the media into the intima in chronic vascular disease. The surface expression of the adhesion molecules is regulated by intracellular free calcium concentration and protein kinase C. We studied the effects of hyperlipoproteinema and hyperglycemia, known risk factors of chronic vascular disease, on the surface expression of adhesion molecules on endothelial cells [12]. We could show that different isozymes of the protein kinase C family are responsible for phosphorylating and regulating the adhesion molecules [13]. We also addressed the question whether or not binding to adhesion molecules affects the intracellular signalling cascade and could show that binding to the selectin family of adhesion molecules triggers tyrosine phosphorylation in white blood cells [14].Using FACS-analysis, we assessed the expression of adhesion molecules on leukocytes in patients with Wegener's Granulomatosis. We found that during exacerbation of the disease there is increased expression of the integrin receptors LFA-1 and VLA-4 on granulocytes and monocytes in these patients [11]. Influencing expression of adhesion molecules could be an important therapeutic approach in inflammatory vascular diseases, as well as in chronic vascular diseases. We are therefore investigating the possibilities of an antisense strategy for inhibition of adhesion molecule expression. For the gene transfer, virus-coated liposomes (Sendai virus) are used in cell cultures and in animal models. The aim of these studies is to interfere with the complex alterations in inter-and intracellular signalling in chronic diseases of the vascular wall and to try to re-establish undisturbed cellular communication. In short, our laboratory is dedicated to establish 'who is talking to whom' in the vascular wall. We have encountered inappropriate silence and unacceptable shouting matches between the components. Our goal is the promotion of mutual understanding through reasonable communications.

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“…PTH decreases renal phosphorus reabsorption through internalization of the tubular type 2a sodium-phosphate transporter and by decreasing type 2a sodium-phosphate transporter gene transcription. 1,2 The recently described bone hormone fibroblast growth factor 23 (FGF-23) decreases phosphorus reabsorption through changes in the type 2a sodium-phosphate transporter and suppresses 1␣-hydroxylase activity in the kidney. 3,4 Circulating FGF-23 levels are increased in patients with primary, 5,6 secondary, [7][8][9] and persistent hyperparathyroidism 10,11 and contribute to the development of early posttransplantation hypophosphatemia.…”

mentioning

confidence: 99%

Phosphatemic Effect of Cinacalcet in Kidney Transplant Recipients With Persistent Hyperparathyroidism

Serra

Wuhrmann

Wüthrich

2008

American Journal of Kidney Diseases

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Parathyroid hormone action on phosphate transporter mRNA and protein in rat renal proximal tubules

Cited by 123 publications

References 0 publications

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Molecular mechanisms in renal phosphate reabsorption

Phosphatemic Effect of Cinacalcet in Kidney Transplant Recipients With Persistent Hyperparathyroidism

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