Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: Potential mechanism for uremic vascular calcification

• Type of Material: Article
• Authors: Koba A Lomashvili, Emory University; P Garg, Emory University; S Narisawa, Burnham Institute for Medical Research; JL Millan, Burnham Institute for Medical Research; W Charles O'Neill, Emory University
• Language: English
• Date: 2008-05
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2008 International Society of Nephrology
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://www.nature.com/ki/journal/v73/n9/full/ki200826a.html
• Title of Journal or Parent Work: Kidney International
• ISSN: 0085-2538
• Volume: 73
• Issue: 9
• Start Page: 1024
• End Page: 1030
• Grant/Funding Information: Dr Garg was supported by NIH Training Grant DK07656 and Dr Lomashvili was supported by an Amgen Nephrology Fellowship.; Supported by grants DK69681 (WCO), DE12889 (JLM), AR47908 (JLM), from the National Institutes of Health and a grant from the Genzyme Renal Innovations Program (WCO).
• Keywords: vascular calcification
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Physiology

Abstract

Pyrophosphate is a potent inhibitor of medial vascular calcification where its level is controlled by hydrolysis via a tissue-nonspecific alkaline phosphatase (TNAP). We sought to determine if increased TNAP activity could explain the pyrophosphate deficiency and vascular calcification seen in renal failure. TNAP activity increased twofold in intact aortas and in aortic homogenates from rats made uremic by feeding adenine or by 5/6 nephrectomy. Immunoblotting showed an increase in protein abundance but there was no increase in TNAP mRNA assessed by quantitative polymerase chain reaction. Hydrolysis of pyrophosphate by rat aortic rings was inhibited about half by the nonspecific alkaline phosphatase inhibitor levamisole and was reduced about half in aortas from mice lacking TNAP. Hydrolysis was increased in aortic rings from uremic rats and all of this increase was inhibited by levamisole. An increase in TNAP activity and pyrophosphate hydrolysis also occurred when aortic rings from normal rats were incubated with uremic rat plasma. These results suggest that a circulating factor causes pyrophosphate deficiency by regulating TNAP activity and that vascular calcification in renal failure may result from the action of this factor. If proven by future studies, this mechanism will identify alkaline phosphatase as a potential therapeutic target.