Matrix Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease

Armand M G Jaminon,Magnus Söderberg,Peter Stenvinkel,Hannes Olauson,Leon J Schurgers,Abdul Rashid Qureshi,Lu Dai,Jonaz Ripsweden,Anna Witasp,Pieter Evenepoel

doi:10.1038/s41598-020-63013-8

Abstract

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. In 141 CKD stage 5 patients, CAC score was significantly increased in the highest tertile of dp-ucMGP (p = 0.002), and a high medial VC score was associated with elevated dp-ucMGP levels. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0–1312]) compared to patients carrying a T allele (median 0 [range 0–966] AU). These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Additionally, high vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Taken together, our results support that MGP is involved in the pathogenesis of VC.

Highlights

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition
Matrix Gla protein (MGP) is a vitamin K dependent protein (VKDP) that is involved in the inhibition of vascular calcification (VC)
Vitamin K deficiency is frequently encountered in Chronic kidney disease (CKD), which is associated with increased plasma levels of dephosphorylated uncarboxylated MGP plasma levels[6,7]

Summary

Introduction

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0–1312]) compared to patients carrying a T allele (median 0 [range 0–966] AU) These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. High vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Vitamin K is a co-factor for the enzyme γ-glutamyl carboxylase that converts glutamic acid (Glu) into γ-carboxyglutamic acid (Gla) residues[2] This conversion is critical for the activation of MGP. We link MGP genetics (SNPs), transcription (mRNA) and protein data (immunohistochemistry and plasma levels) to clinical vascular phenotype (CAC and histology)

Methods

Results

Conclusion