Stimulation of Na-dependent phosphate transport by platelet-derived growth factor in rat aortic smooth muscle cells

Kakita, Ayako; Suzuki, Atsushi; Nishiwaki, Keiko; Ono, Yuka; Kotake, Motoko; Ariyoshi, Yoh; Miura, Yoshitaka; ltoh, Mitsuyasu; Oiso, Yutaka

doi:10.1016/j.atherosclerosis.2003.12.039

Cited by 42 publications

(34 citation statements)

References 30 publications

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“…Many osteotropic factors regulate phosphate uptake are associated with osteogenic differentiation and mineralization in osteoblasts. Upregulation of Pit-1 may be a common mechanism by which osteotropic factors, such as BMP-2, TGF-β and PDGF, promote biomineralization [20,21,32]. Consistent with these studies, we previously reported that phosphate uptake via Pit-1 was also required for SMC calcification, suggesting a crucial role of Pit-1 in osteogenic differentiation and mineralization of SMC [8].…”

Section: Discussionsupporting

confidence: 71%

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BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells

2008

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Vascular calcification is associated with increased risk of cardiovascular events that are the most common cause of death in patients with end-stage renal disease. Clinical and experimental studies indicate that hyperphosphatemia is a risk factor for vascular calcification and cardiovascular mortality in these patients. Our previous studies demonstrated that phosphate transport through the type III sodium-dependent phosphate cotransporter, Pit-1, was necessary for phosphate-induced calcification and osteochondrogenic phenotypic change in cultured human smooth muscle cells (SMC). BMP-2 is a potent osteogenic protein required for osteoblast differentiation and bone formation that has been implicated in vascular calcification. In the present study, we have examined the effects of BMP-2 on human SMC calcification in vitro. We found that treatment of SMC with BMP-2 enhanced elevated phosphate-induced calcification, but did not induce calcification under normal phosphate conditions. mRNAs for BMP receptors, including ALK2, ALK3, ALK6, BMPR-II, ActR-IIA and ActR-IIB were all detected in human SMCs. Mechanistically, BMP-2 dose-dependently stimulated phosphate uptake in SMC (200 ng/ml BMP-2 vs vehicle: 13.94 vs 7.09 nmol/30 min/mg protein, respectively). Real-time PCR and Western blot revealed the upregulation of Pit-1 mRNA and protein levels, respectively, by BMP-2. More importantly, inhibition of phosphate uptake by a competitive inhibitor of sodiumdependent phosphate cotransport, phosphonoformic acid, abrogated BMP-2-induced calcification. These results indicate that phosphate transport via Pit-1 is crucial in BMP-2-regulated SMC calcification. In addition, BMP-2 induced Runx2 and inhibited SM22 expression, indicating that it promotes osteogenic phenotype transition in these cells. Thus, BMP-2 may promote vascular calcification via increased phosphate uptake and induction of osteogenic phenotype modulation in SMC.

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Section: Discussionsupporting

confidence: 71%

“…Csiszar et al showed that ERK and PKC play important roles in BMP-2-induced proinflammatory phenotype in endothelial cells [19]. In addition, JNK and PI3-kinase are also involved in BMP-2-upregulated Pit-1 expression [20,21].…”

Section: Discussionmentioning

confidence: 99%

BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells

2008

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“…2). The phosphatidylinositol (PI) 3-kinase pathway is another important intracellular signaling mechanism previously shown to influence the stimulation of solute transport activities in response to activated PDGF receptors in A-10 VSMC [10]. Wortmannin, a specific inhibitor of PI 3-kinase [29], significantly reduced the change in Pi transport induced by AVP in A-10 cells (Table 2).…”

Section: Resultsmentioning

confidence: 98%

“…PI 3-kinase is important in particular for cell migration, actin reorganization, and prevention of cell death of apoptosis [36]. We have recently shown that PI 3-kinase and S 6 kinase are involved in the mechanism of PDGF-induced enhancement of Pi transport in A-10 cells [10]. In the present study, we showed that wortmannin, a selective PI 3-kinase inhibitor, significantly decreased Pi transport stimulation induced by AVP in A-10 cells.…”

Section: Discussionmentioning

confidence: 99%

“…After vascular injury, VSMC at the artery media is activated and migrates to the intima, where the cells proliferate and secrete extracellular matrix components [1]. We have recently reported that platelet-derived growth factor (PDGF) stimulates Pi transport activity through the expression of type III Na-dependent PiT, which is considered to be essential for the mineralization of bone tissues [3,9], in rat A-10 aortic VSMC [10]. However, the precise mechanism of the enhancement of Pi transport activity by extracellular stimuli in VSMC has yet to be fully elucidated.…”

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confidence: 99%

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Vasopressin Stimulates Na-dependent Phosphate Transport and Calcification in Rat Aortic Smooth Muscle Cells

et al. 2007

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Abstract. We investigated the effect of arginine vasopressin (AVP) on inorganic phosphate (Pi) transport in A-10 rat aortic vascular smooth muscle cells (VSMCs). AVP time-and dose-dependently stimulated Na-dependent Pi transport in A-10 cells. This stimulatory effect of AVP on Pi transport was markedly suppressed by V1 receptor antagonist. A protein kinase C (PKC) inhibitor calphostin C partially suppressed the stimulatory effect of AVP. The selective inhibitors of cJun-NH 2 -terminal mitogen-activated protein (MAP) kinase (Jun kinase) attenuated AVP-induced Pi transport, but Erk kinase or p38 MAP kinase inhibitors did not. Wortmannin, a phosphatidylinositol (PI) 3-kinase inhibitor, suppressed AVP-induced Pi transport. Rapamycin, a selective inhibitor of S 6 kinase, reduced this effect of AVP, while Akt kinase inhibitor did not. The combination of inhibitors for PKC, Jun kinase and PI 3-kinase completely suppressed the AVPenhanced Pi transport. Furthermore, AVP rescued the VSMC from high phosphate-induced cell death and enhanced mineralization of these cells. In summary, these results suggest that AVP stimulates both Na-dependent Pi transport and mineralization in VSMCs. The mechanism is mediated by the activation of multiple signaling pathways including PKC, PI 3-kinase, S 6 kinase and Jun kinase.

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Genetic Screening and Functional Characterization ofPDGFRBMutations Associated with Basal Ganglia Calcification of Unknown Etiology

et al. 2014

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Three causal genes for Idiopathic Basal Ganglia Calcification (IBGC) have been identified. Most recently, mutations in PDGFRB, encoding a member of the platelet-derived growth factor receptor family type β, and PDGFB, encoding PDGF-B, the specific ligand of PDGFRβ, were found implicating the PDGF-B/PDGFRβ pathway in abnormal brain calcification. In this study we aimed to identify and study mutations in PDGFRB and PDGFB in a series of 26 patients from the Mayo Clinic Florida Brain Bank with moderate to severe basal ganglia calcification (BCG) of unknown etiology. No mutations in PDGFB were found. However, we identified one mutation in PDGFRB, p.R695C located in the tyrosine kinase domain, in one BGC patient. We further studied the function of p.R695C mutant PDGFRβ and two previously reported mutants, p.L658P and p.R987W PDGFRβ in cell culture. We show that, in response to PDGF-BB stimulation, the p.L658P mutation completely suppresses PDGFRβ autophosphorylation whereas the p.R695C mutation results in partial loss of autophosphorylation. For the p.R987W mutation, our data suggest a different mechanism involving reduced protein levels. These genetic and functional studies provide the first insight into the pathogenic mechanisms associated with PDGFRB mutations and provide further support for a pathogenic role of PDGFRB mutations in BGC.

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Stimulation of Na-dependent phosphate transport by platelet-derived growth factor in rat aortic smooth muscle cells

Cited by 42 publications

References 30 publications

BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells

BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells

Vasopressin Stimulates Na-dependent Phosphate Transport and Calcification in Rat Aortic Smooth Muscle Cells

Genetic Screening and Functional Characterization ofPDGFRBMutations Associated with Basal Ganglia Calcification of Unknown Etiology

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