Uremic serum induced calcification of human aortic smooth muscle cells is a regulated process involving Klotho and RUNX2

Date

2019-07-24

Advisors

Journal Title

Journal ISSN

ISSN

Volume Title

Publisher

Portland Press

Type

Article

Peer reviewed

Yes

Abstract

Vascular calcification (VC) is common in subjects with chronic kidney disease (CKD) and is associated with increased cardiovascular risk. It is an active process involving trans-differentiation of arterial smooth muscle cells (SMCs) into osteogenic phenotype. We investigated the ability of serum from CKD subjects to induce calcification in human SMCs in vitro (calcific potential of sera: CP), and associated changes in expression of RUNX2, SM22a and Klotho. Sera from subjects with CKD (18 stage 3, 17 stage 4/5, and 29 stage 5D) and 20 controls were added to human cultured SMCs and CP quantified. The CP of CKD sera was greater ( p<0.01 ) than that of controls, though not influenced by CKD stage. MDRD-4 eGFR ( p<0.001 ), serum phosphate ( p= 0.042 ), RANKL ( p= 0.001 ), PTH ( p= 0.014 ) and HDL/Cholesterol ratio ( p= 0.026 ) were independent predictors of CP accounting for 45% of variation. Adding calcification buffer (CB: calcium chloride [7mM] and β glycerophosphate [7mM]) increased the CP of control sera to approximate that of CKD sera. CP of CKD sera was unchanged. CKD sera increased RUNX2 expression ( p<0.01 ) in human SMCs and decreased SM22a expression ( p<0.05 ). Co-incubating control but not CKD serum with CB further increased RUNX2 expression ( p<0.01 ). Both SM22a and Klotho expression decreased significantly ( p<0.01 ) in the presence of CKD serum, and were virtually abolished with Stage 5D sera. These findings support active regulation by CKD serum of in vitro VC by induction of RUNX2 and suppression of SM22a and Klotho.

Description

open access article

Keywords

Uraemic serum, Chronic kidney disease, Vascular calcification, Klotho, RUNX2, Human aortic smooth muscle cells

Citation

Patidar, A., Singh, D., Thakur, S., Farrington, K., Baydoun, A. (2019) Uremic serum induced calcification of human aortic smooth muscle cells is a regulated process involving Klotho and RUNX2. Bioscience Reports, 39, pp.1-11.

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Research Institute

Leicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)