PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet

Yamada, S.; Leaf, Elizabeth M.; Chia, Jia Jun; Cox, Timothy C.; Speer, Mei Y.; Giachelli, Cecilia M.

doi:10.1016/j.kint.2018.05.015

Cited by 42 publications

(34 citation statements)

References 52 publications

(71 reference statements)

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“…The pattern and localization of calcification detected in this study are consistent with that observed in previous studies using this uremic DBA/2 mouse model of arterial medial calcification 26,[43][44][45] ; that is, calcification was focally distributed and 'patchy'. In human specimens where larger calcified deposits have been observed, 'patchy' or focally distributed calcifications have also been detected 5,[46][47][48] .…”

Section: Discussionsupporting

confidence: 91%

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

Borland

Facchi

Adamson

et al. 2020

Preprint

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Arterial medial calcification is an independent risk factor for mortality in chronic kidney disease. We previously reported that knock-down of PKCα expression increases high phosphate-induced mineral deposition by vascular smooth muscle cells in vitro. This new study tests the hypothesis that PKCα regulates uremia-induced medial calcification in vivo. Female wild-type and PKCα -/mice underwent a two-stage subtotal nephrectomy and were fed a high phosphate diet for 8 weeks. X-ray micro computed tomography demonstrated that uremia-induced medial calcification was increased in the abdominal aorta and aortic arch of PKCα -/mice compared to wild-types. Blood urea nitrogen was also increased in PKCα -/mice compared to wild-types; there was no correlation between blood urea nitrogen and calcification in PKCα -/mice.Phosphorylated SMAD2 immunostaining was detected in calcified aortic arches from uremic PKCα -/mice; the osteogenic marker Runx2 was also detected in these areas. No phosphorylated SMAD2 staining were detected in calcified arches from uremic wild-types. PKCα knock-down increased TGF-β1-induced SMAD2 phosphorylation in vascular smooth muscle cells in vitro, whereas the PKCα activator prostratin decreased SMAD2 phosphorylation. In conclusion, loss of PKCα increases uremia-induced medial calcification. The PKCα/TGF-β signaling axis could therefore represent a new therapeutic target for arterial medial calcification in chronic kidney disease.

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Section: Discussionsupporting

confidence: 91%

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

Borland

Facchi

Adamson

et al. 2020

Preprint

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“…These two transporters were considered to play a redundant role in phosphate-induced osteoinduction in VSMCs [ 88 ]. However, the recent findings suggest that PIT2 may even protect against vascular calcification by the up-regulation of osteoprotegerin [ 89 ], a key regulator of bone metabolism and inhibitor of vascular calcification [ 31 , 90 ].…”

Section: Signaling Pathways Regulating Vsmcs Calcification During Higmentioning

confidence: 99%

Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

Voelkl

Läng

Eckardt

et al. 2019

Cell. Mol. Life Sci.

139

202

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Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.

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“…Rodent models of CKD are used widely to study arterial medial calcification and include interventions such as vitamin D 3 overload, adenine administration, and 5/6 nephrectomy [ 14 , 15 , 16 ]. The calcification(s) observed in these models is often distributed focally and is ‘patchy’ in nature [ 17 , 18 ], which is similar to the patterns of calcification observed in specimens from patients with CKD [ 19 , 20 , 21 ]. Atherosclerotic apolipoprotein E knock-out (ApoE −/− ) and low-density lipoprotein receptor knock-out (LDLR −/− ) mice are popular models to study the development of arterial intimal calcification [ 22 ], with both micro- and macro-calcifications frequently detected in severe atheromatous plaques [ 23 , 24 ], as is the case in humans.…”

Section: Rodent Models Of Arterial Medial and Intimal Calcificatiomentioning

confidence: 83%

X-ray Micro-Computed Tomography: An Emerging Technology to Analyze Vascular Calcification in Animal Models

Borland

Ashton

Francis

et al. 2020

IJMS

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Vascular calcification describes the formation of mineralized tissue within the blood vessel wall, and it is highly associated with increased cardiovascular morbidity and mortality in patients with chronic kidney disease, diabetes, and atherosclerosis. In this article, we briefly review different rodent models used to study vascular calcification in vivo, and critically assess the strengths and weaknesses of the current techniques used to analyze and quantify calcification in these models, namely 2-D histology and the o-cresolphthalein assay. In light of this, we examine X-ray micro-computed tomography (µCT) as an emerging complementary tool for the analysis of vascular calcification in animal models. We demonstrate that this non-destructive technique allows us to simultaneously quantify and localize calcification in an intact vessel in 3-D, and we consider recent advances in µCT sample preparation techniques. This review also discusses the potential to combine 3-D µCT analyses with subsequent 2-D histological, immunohistochemical, and proteomic approaches in correlative microscopy workflows to obtain rich, multifaceted information on calcification volume, calcification load, and signaling mechanisms from within the same arterial segment. In conclusion we briefly discuss the potential use of µCT to visualize and measure vascular calcification in vivo in real-time.

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PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet

Cited by 42 publications

References 52 publications

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

X-ray Micro-Computed Tomography: An Emerging Technology to Analyze Vascular Calcification in Animal Models

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