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

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BACKGROUND:Chronic kidney disease (CKD) is associated with arterial medial calcification which plays a major role in the pathogenesis of cardiovascular disease in this population. Several factors are known to promote soft tissue and accelerated arterial calcification in CKD including systemic inflammation, altered calcium and phosphate homeostasis, hypertension, and deficiency of endogenous calcification inhibitors. The ABCC6 transporter (ATP-binding cassette subfamily C number 6), also known as multidrug resistance-associated protein 6 (MRP6), is highly expressed in the liver and kidney. Mutation of ABCC6 results in pseudoxanthoma elasticum, an inherited disorder characterized by arterial and soft tissue calcification. Given the prevalence of arterial medial calcification in CKD, the present study was undertaken to test the hypothesis that CKD may lead to acquired ABCC6 deficiency. METHODS:CKD was induced via 5/6 nephrectomy in male Sprague-Dawley rats and by adenine-containing diet to cause chronic interstitial nephropathy in female DBA/2J mice. Sham-operated rats and mice fed regular diet served as controls. Liver and kidney tissues were harvested and processed for ABCC6 protein and mRNA analysis. RESULTS:ABCC6 protein levels were significantly reduced in the liver and kidney tissues from CKD rats and mice. However, ABCC6 mRNA levels were unchanged, pointing to post-transcriptional or post-translational mechanisms for the observed ABCC6 deficiency. Additionally, plasma levels of the calcification inhibitor fetuin-A were significantly decreased in CKD animals compared to controls. CONCLUSIONS:CKD results in acquired ABCC6 transporter deficiency. To our knowledge this abnormality has not been previously reported and may contribute to CKD-associated vascular and soft tissue calcification.

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