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

Nishiwaki-Yasuda, Keiko; Suzuki, Atsushi; Kakita, Ayako; Sekiguchi, Sahoko; Asano, Shogo; Nishii, Kazuhiro; Nagao, Shizuko; Oiso, Yutaka; Itoh, Mitsuyasu

doi:10.1507/endocrj.k06-093

Cited by 18 publications

(14 citation statements)

References 46 publications

(61 reference statements)

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“…These stimulations are generally recognized as characteristic of cardioprotective agents. Several studies [6], [53], [54] have indicated that PI3-K/Akt activation inhibited the osteoblastic differentiation of VSMCs, and the results of our present experiment supported this conclusion. The relationship between ERK activation and osteoblastic of VSMCs is still controversial.…”

Section: Discussionsupporting

confidence: 90%

Apelin Attenuates the Osteoblastic Differentiation of Vascular Smooth Muscle Cells

Shan

Cui

et al. 2011

PLoS ONE

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Vascular calcification, which results from a process osteoblastic differentiation of vascular smooth muscle cells (VSMCs), is a major risk factor for cardiovascular morbidity and mortality. Apelin is a recently discovered peptide that is the endogenous ligand for the orphan G-protein-coupled receptor, APJ. Several studies have identified the protective effects of apelin on the cardiovascular system. However, the effects and mechanisms of apelin on the osteoblastic differentiation of VSMCs have not been elucidated. Using a culture of calcifying vascular smooth muscle cells (CVMSCs) as a model for the study of vascular calcification, the relationship between apelin and the osteoblastic differentiation of VSMCs and the signal pathway involved were investigated. Alkaline phosphatase (ALP) activity and osteocalcin secretion were examined in CVSMCs. The involved signal pathway was studied using the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, the phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002, and APJ siRNA. The results showed that apelin inhibited ALP activity, osteocalcin secretion, and the formation of mineralized nodules. APJ protein was detected in CVSMCs, and apelin activated ERK and AKT (a downstream effector of PI3-K). Suppression of APJ with siRNA abolished the apelin-induced activation of ERK and Akt. Furthermore, inhibition of APJ expression, and the activation of ERK or PI3-K, reversed the effects of apelin on ALP activity. These results showed that apelin inhibited the osteoblastic differentiation of CVSMCs through the APJ/ERK and APJ/PI3-K/AKT signaling pathway. Apelin appears to play a protective role against arterial calcification.

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Section: Discussionsupporting

confidence: 90%

Apelin Attenuates the Osteoblastic Differentiation of Vascular Smooth Muscle Cells

Shan

Cui

et al. 2011

PLoS ONE

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“…Similarly, Pit-1 expression also does not change during the calcification induced with protein kinase A activators [10]. On the other hand, positive correlations have been reported by some authors for calcification and expression of Pit-1 RNA or protein [7,15,17,20,23]. Therefore, an increase in Pi transport rate or in Pit-1 expression is not a universal requirement for the onset of calcification.…”

Section: Discussionmentioning

confidence: 84%

Vascular smooth muscle cell calcification and SLC20 inorganic phosphate transporters: effects of PDGF, TNF-α, and Pi

Villa‐Bellosta

Levi

Sorribas

2009

Pflugers Arch - Eur J Physiol

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Pi transport by vascular smooth muscle cells (VSMC) has been proposed to play an important role in the pathogenesis of vascular calcification. In this study, we have determined the correlation between calcification induced by Pi, platelet-derived growth factor (PDGF)-BB, and tumor necrosis factor-alpha and Pi transport activity in primary cultures of rat aortic VSMC. These agents induced calcification and increased the expression of Cbfa1, Msx2, and Bmp2 osteogene messenger RNA in rat aortic VSMC, while Pi transport rate was not modified per milligram of protein. Only PDGF increased Pi transport when it was expressed per unit of DNA, as PDGF also increased total cell protein by 100%, while DNA content and number of cells were not modified. PDGF increased the expression of the Pi transporter, Pit-1, but membrane protein biotinylation showed that Pit-1 abundance was not modified in the cell surface. Immunofluorescence revealed that, under basal conditions, Pit-1 is only slightly expressed at the cell membrane, but strongly expressed inside the cell. The intracellular signal colocalizes with endoplasmic reticulum (ER) markers, and PDGF increases Pit-1 expression in the ER but not the cell membrane. In conclusion, Pi transport across the plasma membrane does not correlate directly with calcification, but the expression of Pit-1 in the ER opens new possibilities for the study of the pathogenesis of vascular calcification.

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“…[41][42][43][44] Pi influx is believed to be mediated by NaPi-3 group of Na ϩ -coupled transporters (Pit-1 and Pit-2) in vascular smooth muscle cells (VSMC). 46 Runx2 expression has been postulated to be an early step of mineralization for osteoblasts and may represent ectopic osteogenesis when expressed in other cells. [47][48][49] Pit1 and Pit2 mRNA was increased in Kl Ϫ/Ϫ and decreased in Tg-Kl compared with WT mice ( Figure 4A).…”

Section: Pi Uptake and Pi-induced Mineralization And Dedifferentiatiomentioning

confidence: 99%

“…46,91,92 The cells were treated with Pi and/or soluble Klotho protein (amino acid number 31 to 982) as previous described. 36 At given time points, the cells were harvested for Von Kossa staining, OCPC assay, RNA extraction, and for 32 P-phosphate and 45 Ca uptake (detailed protocol in Supplemental Methods).…”

Section: Cell Culturementioning

confidence: 99%

Klotho Deficiency Causes Vascular Calcification in Chronic Kidney Disease

Hu¹,

Shi²,

Zhang³

et al. 2011

Journal of the American Society of Nephrology

793

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

Cited by 18 publications

References 46 publications

Apelin Attenuates the Osteoblastic Differentiation of Vascular Smooth Muscle Cells

Apelin Attenuates the Osteoblastic Differentiation of Vascular Smooth Muscle Cells

Vascular smooth muscle cell calcification and SLC20 inorganic phosphate transporters: effects of PDGF, TNF-α, and Pi

Klotho Deficiency Causes Vascular Calcification in Chronic Kidney Disease

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