Characterization of Phosphate Transport in Rat Vascular Smooth Muscle Cells

Villa‐Bellosta, Ricardo; Bogaert, Yolanda E.; Levi, Moshe; Sorribas, Vı́ctor

doi:10.1161/atvbaha.106.132266

Cited by 115 publications

(158 citation statements)

References 33 publications

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“…In an attempt to dissect possible mechanisms for insulin effect on calcification, we found that insulin induces phosphate transport into VSMC. Recently, the kinetic and molecular characteristics of phosphate transport in VSMC have been analyzed in detail, showing that Na-dependent uptake relies exclusively on type III sodium-dependent phosphate co-transporters Pit-1 and Pit-2 (21). Here, we have demonstrated that this is due to an increase in capacity but not affinity for phosphate transport, and may be explained mainly by insulin induction of Pit-2, and to a lesser extent Pit-1.…”

Section: Discussionmentioning

confidence: 54%

Insulin attenuates vascular smooth muscle calcification but increases vascular smooth muscle cell phosphate transport

et al. 2007

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Medial artery vascular smooth muscle cell (VSMC) calcification increases the risk of cardiovascular mortality in type 2 diabetes. However, the influence of insulin on VSMC calcification is unclear. We explored the effects of insulin on rat VSMC calcification in vitro and found that in a dose-dependent fashion, insulin attenuates VSMC calcification induced by high phosphate conditions as quantified by the OCPC method. In an in vitro model of insulin resistance in which cells are exposed to elevated insulin concentrations and the PI 3-kinase pathway is selectively inhibited, increased VSMC calcification was observed, suggesting that the PI 3-kinase pathway is involved in this attenuating effect of insulin. We postulated that insulin may also have an effect on phosphate or calcium transport in VSMC. We found that insulin increases phosphate transport at 3 hr and 24 hr. This effect was mediated by increased V max for phosphate transport but not K m . Because type III sodium-phosphate co-transporters Pit-1 and Pit-2 are found in VSMC, we examined their expression by Western blot and real-time RT-PCR. Insulin stimulates Pit-1 mRNA modestly (*p<0.01 vs. control), an effect mediated by PD98059 but not by wortmannin. Pit-1 protein expression is induced by insulin, an effect also mediated by PD98059 (*p<0.001 vs. insulin alone). Results for Pit-2 were mixed. Our results suggest a role for insulin in attenuating VSMC calcification which may be disrupted in selective insulin signaling impairment seen in insulin resistance. This effect of insulin contrasts with its effect to induce phosphate transport in VSMC.

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Section: Discussionmentioning

confidence: 54%

Insulin attenuates vascular smooth muscle calcification but increases vascular smooth muscle cell phosphate transport

et al. 2007

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“…[3][4]7 NaPi-3 proteins (Pit1 and Pit2) are broadly expressed and believed to play housekeeping as well as pathologic roles in different cells. 70 -73 Extracellular Pi stimulates calcification in VSMC through inorganic Pi influx by NaPi-3 [73][74][75] and cell- surface Pit2 reorganization. 73,76 High ambient Pi accelerates mineralization 44,49 and stimulates surrogate markers of osteogenesis in VSMC, 49,77 spawning the hypothesis that high Pi stimulates "ossification" of VMSC.…”

Section: Pathogenic Role Of Klotho In Progression Of Ckd and Its Compmentioning

confidence: 99%

Klotho Deficiency Causes Vascular Calcification in Chronic Kidney Disease

Hu¹,

Shi²,

Zhang³

et al. 2011

Journal of the American Society of Nephrology

807

877

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Soft-tissue calcification is a prominent feature in both chronic kidney disease (CKD) and experimental Klotho deficiency, but whether Klotho deficiency is responsible for the calcification in CKD is unknown. Here, wild-type mice with CKD had very low renal, plasma, and urinary levels of Klotho. In humans, we observed a graded reduction in urinary Klotho starting at an early stage of CKD and progressing with loss of renal function. Despite induction of CKD, transgenic mice that overexpressed Klotho had preserved levels of Klotho, enhanced phosphaturia, better renal function, and much less calcification compared with wild-type mice with CKD. Conversely, Klotho-haploinsufficient mice with CKD had undetectable levels of Klotho, worse renal function, and severe calcification. The beneficial effect of Klotho on vascular calcification was a result of more than its effect on renal function and phosphatemia, suggesting a direct effect of Klotho on the vasculature. In vitro, Klotho suppressed Na ϩ -dependent uptake of phosphate and mineralization induced by high phosphate and preserved differentiation in vascular smooth muscle cells. In summary, Klotho is an early biomarker for CKD, and Klotho deficiency contributes to soft-tissue calcification in CKD. Klotho ameliorates vascular calcification by enhancing phosphaturia, preserving glomerular filtration, and directly inhibiting phosphate uptake by vascular smooth muscle. Replacement of Klotho may have therapeutic potential for CKD.

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“…A number of studies demonstrate a role for PiT1 in osteoblast-and chondrocyte-mediated mineralization (95)(96)(97). PiT1 expressed on matrix vesicles derived from the parent cell provides phosphate needed for mineralization.…”

Section: Pit1mentioning

confidence: 99%

Clinical Consequences of Mutations in Sodium Phosphate Cotransporters

Lederer

Miyamoto

2012

Clinical Journal of the American Society of Nephrology

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SummaryThree families of sodium phosphate cotransporters have been described. Their specific roles in human health and disease have not been defined. Review of the literature reveals that the type II sodium phosphate cotransporters play a significant role in transepithelial transport in a number of tissues including kidney, intestine, salivary gland, mammary gland, and lung. The type I transporters seem to play a major role in renal urate handling and mutations in these proteins have been implicated in susceptibility to gout. The ubiquitously expressed type III transporters play a lesser role in phosphate homeostasis but contribute to cellular phosphate uptake, mineralization, and inflammation. The recognition of species differences in the expression, regulation, and function of these transport proteins suggests an urgent need to find ways to study them in humans.

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Characterization of Phosphate Transport in Rat Vascular Smooth Muscle Cells

Cited by 115 publications

References 33 publications

Insulin attenuates vascular smooth muscle calcification but increases vascular smooth muscle cell phosphate transport

Insulin attenuates vascular smooth muscle calcification but increases vascular smooth muscle cell phosphate transport

Klotho Deficiency Causes Vascular Calcification in Chronic Kidney Disease

Clinical Consequences of Mutations in Sodium Phosphate Cotransporters

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