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Author Notes:

Dr. Lomashvili at Emory University, Renal Division WMB 338, 1639 Pierce Dr., Atlanta, GA 30322, klomash@emory.edu.

Drs. Lomashvili and O’Neill are co-inventors of a patent owned by Emory University related to the therapeutic use of pyrophosphate.

The other authors have nothing to disclose.

Subject:

Research Funding:

Supported by grants DK069681 and DK079176 from the National Institutes of Health.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Urology & Nephrology
  • alkaline phosphatase
  • ectonucleotide pyrophosphorylase pyrophosphatase
  • pyrophosphate
  • transplantation
  • vascular calcification
  • ALKALINE-PHOSPHATASE
  • INORGANIC PYROPHOSPHATE
  • MINERALIZATION
  • PATHOGENESIS
  • METABOLISM
  • MODEL
  • ANK

Vascular calcification is dependent on plasma levels of pyrophosphate

Tools:

Journal Title:

Kidney International

Volume:

Volume 85, Number 6

Publisher:

, Pages 1351-1356

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Plasma levels of pyrophosphate, an endogenous inhibitor of vascular calcification, are reduced in end-stage renal disease and correlate inversely with arterial calcification. However, it is not known whether the low plasma levels are directly pathogenic or are merely a marker of reduced tissue levels. This was tested in an animal model in which aortas were transplanted between normal mice and Enpp1-/-mice lacking ectonucleotide pyrophosphatase phosphodiesterase, the enzyme that synthesizes extracellular pyrophosphate. Enpp1-/-mice had very low plasma pyrophosphate and developed aortic calcification by 2 months that was greatly accelerated with a high-phosphate diet. Aortas of Enpp1-/-mice showed no further calcification after transplantation into wild-type mice fed a high-phosphate diet. Aorta allografts of wild-type mice calcified in Enpp1-/-mice but less so than the adjacent recipient Enpp1-/-aorta. Donor and recipient aortic calcium contents did not differ in transplants between wild-type and Enpp1-/-mice, demonstrating that transplantation per se did not affect calcification. Histology revealed medial calcification with no signs of rejection. Thus, normal levels of extracellular pyrophosphate are sufficient to prevent vascular calcification, and systemic Enpp1 deficiency is sufficient to produce vascular calcification despite normal vascular extracellular pyrophosphate production. This establishes an important role for circulating extracellular pyrophosphate in preventing vascular calcification.

Copyright information:

© 2013 International Society of Nephrology.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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