Chronic Kidney Disease Results in Deficiency of ABCC6, the Novel Inhibitor of Vascular Calcification

Lau, Wei Ling; Liu, Shuman; Vaziri, Nosratola D.

doi:10.1159/000365014

Cited by 29 publications

(28 citation statements)

References 34 publications

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“…The MGP knockout mouse shows spontaneous calcification of arteries and cartilage [74]. Interestingly, a murine model of CKD displayed low levels of Abcc6 protein but normal Abcc6 mRNA levels – suggesting a post-transcriptional or post-translational deficiency [75]. …”

Section: Etiologymentioning

confidence: 99%

Pseudoxanthoma elasticum

Germain

2017

Orphanet J Rare Dis

138

147

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Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic mineralization that is most apparent in the elastic tissues of the skin, eyes and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance. The first clinical sign of PXE is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules coalesce, and the skin becomes loose and wrinkled. The mid-dermal elastic fibers are short, fragmented, clumped and calcified. Dystrophic calcification of Bruch’s membrane, revealed by angioid streaks, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. Ischemic strokes have been reported. PXE is a metabolic disease in which circulating levels of an anti-mineralization factor are low. There is good evidence to suggest that the factor is inorganic pyrophosphate (PPi), and that the circulating low levels of PPi and decreased PPi/Pi ratio result from the lack of ATP release by hepatocytes harboring the mutant ABCC6 protein. However, the substrate(s) bound, transported or modulated by the ABCC6 protein remain unknown. More than 300 sequence variants of the ABCC6 gene have been identified. There is no cure for PXE; the main symptomatic treatments are vascular endothelial growth factor inhibitor therapy (for ophthalmic manifestations), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), and vascular surgery (for severe cardiovascular manifestations). Future treatment options may include gene therapy/editing and pharmacologic chaperone therapy.

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Section: Etiologymentioning

confidence: 99%

Pseudoxanthoma elasticum

Germain

2017

Orphanet J Rare Dis

138

147

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“…It forms stable circulating complexes containing calcium, phosphorus, and acidic proteins (calciprotein particles), which can be cleared by the liver [62]. Low serum fetuin-A correlates with cardiovascular death in dialysis patients [63, 64] and may be due to acquired deficiency of the hepatic ABCC6 transporter in CKD [65]. …”

Section: Deficiency Of Calcification Inhibitorsmentioning

confidence: 99%

The Cerebrovascular-Chronic Kidney Disease Connection: Perspectives and Mechanisms

Lau

Huisa

Fisher

2016

Transl. Stroke Res.

Self Cite

122

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Chronic kidney disease (CKD) is an independent risk factor for the development of cerebrovascular disease, particularly small vessel disease which can manifest in a variety of phenotypes ranging from lacunes to microbleeds. Small vessel disease likely contributes to cognitive dysfunction in the CKD population. Non-traditional risk factors for vascular injury in uremia include loss of calcification inhibitors, hyperphosphatemia, increased blood pressure variability, elastinolysis, platelet dysfunction, and chronic inflammation. In this review, we discuss the putative pathways by which these mechanisms may promote cerebrovascular disease and thus increase risk of future stroke in CKD patients.

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“…50 In rat models of CKD, there was evidence of decreased Abcc6 protein levels suggesting that CKD induces an acquired Abcc6 transporter deficiency. 51 The gene NT5E has also has been related to vascular calcification. This gene encodes the glycosyl-phosphatidylinositol-linked plasma membrane CD73 ectoenzyme.…”

Section: Introductionmentioning

confidence: 99%

Vascular calcification: Mechanisms of vascular smooth muscle cell calcification

Leopold

2015

Trends in Cardiovascular Medicine

344

323

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Vascular calcification is highly prevalent and, when present, is associated with major adverse cardiovascular events. Vascular smooth muscle cells play an integral role in mediating vessel calcification by undergoing differentiation to osteoblast-like cells and generating matrix vesicles that serve as a nidus for calcium-phosphate deposition in the vessel wall. Once believed to be a passive process, it is now recognized that vascular calcification is a complex and highly regulated process that involves activation of cellular signaling pathways, circulating inhibitors of calcification, genetic factors, and hormones. This review will examine several of the key mechanisms linking vascular smooth muscle cells to vessel calcification that may be targeted to reduce vessel wall mineralization and, thereby, reduce cardiovascular risk.

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Chronic Kidney Disease Results in Deficiency of ABCC6, the Novel Inhibitor of Vascular Calcification

Cited by 29 publications

References 34 publications

Pseudoxanthoma elasticum

Pseudoxanthoma elasticum

The Cerebrovascular-Chronic Kidney Disease Connection: Perspectives and Mechanisms

Vascular calcification: Mechanisms of vascular smooth muscle cell calcification

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