RGD Reference Report - Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: potential mechanism for uremic vascular calcification. - Rat Genome Database

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

Authors: Lomashvili, KA  Garg, P  Narisawa, S  Millan, JL  O'Neill, WC 
Citation: Lomashvili KA, etal., Kidney Int. 2008 May;73(9):1024-30. Epub 2008 Feb 20.
RGD ID: 2315619
Pubmed: PMID:18288101   (View Abstract at PubMed)
PMCID: PMC3010853   (View Article at PubMed Central)
DOI: DOI:10.1038/ki.2008.26   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
uremia  ISOAlpl (Rattus norvegicus)2315619; 2315619protein:increased expression:aortaRGD 
uremia  IEP 2315619protein:increased expression:aortaRGD 

Objects Annotated

Genes (Rattus norvegicus)
Alpl  (alkaline phosphatase, biomineralization associated)

Genes (Mus musculus)
Alpl  (alkaline phosphatase, liver/bone/kidney)

Genes (Homo sapiens)
ALPL  (alkaline phosphatase, biomineralization associated)


Additional Information