DNMT3A regulates differentiation of osteoblast and autophagy of vascular smooth muscle cells in vascular medial calcification induced by high phosphorus through ERK1/2 signaling

Xiaoying Ma,Dongxue Zhang,Wei Zhou,Meijuan Cheng,Jingjing Jin,Jinsheng Xu,Huiran Zhang,Shenglei Zhang,Lei He,Yaling Bai

doi:10.1590/fst.74021

Abstract

To investigate the effect of DNMT3A in vascular calcification (VC) induced by high phosphorus. The arterial tissues of 12 patients with end stage renal disease (ESRD) and VC and 12 patients with ESRD without VC were collected. Rat vascular smooth muscle cells (VSMCs) were divided into control group, high phosphorus (P) group, P + DMSO group, p-ERK1/2 inhibitor group, DNMT3A group and DNMT3A + P group and P + shRNA-DNMT3A group. Vascular calcification was evaluated by von kossa staining. Cell calcification was evaluated by alizarin red staining. The calcium content was assessed by calcium determination kit. The levels of DNMT3A, Runx2, LC3 and p-ERK1/2 were significantly up-regulated in CKD patients with VC in comparison with those in CKD patients without VC(p<0.05). Moreover, the levels of SM22α and P62 were notably decreased in CKD patients with VC in comparison with those in CKD patients without VC(p<0.05). Similar changes were observed in VSMCs induced by high phosphorus. Knock down of DNMT3A in VSMCs inhibited phenotypic transformation and induced autophagy, then reduced calcification(p<0.05). Moreover, p-ERK1/2 level was downregulated by knock down of DNMT3A in comparison with the control group(p<0.05). In conclusion, DNMT3A regulated high phosphorus induced vascular medial calcification via ERK1/2 signaling.

Highlights

Medial vascular calcification (VC) is one of the common complications in patients with chronic kidney disease (CKD) (Vervloet & Cozzolino, 2017)
Practical Application: Our study suggested that DNA methyltransferases 3A (DNMT3A) was involved in the pathogenesis of medial VC, and DNMT3A regulated high phosphorus
We aimed to examine the effect of DNMT3A on high phosphorus induced VC

Summary

Introduction

Medial vascular calcification (VC) is one of the common complications in patients with chronic kidney disease (CKD) (Vervloet & Cozzolino, 2017). The prevalence of cardiovascular disease (CVD) in patients with CKD is substantially higher than that in the healthy controls, which is strongly associated with VC (Komatsu et al, 2014). The phenotype transformation and autophagy of vascular smooth muscle cells (VSMCs) are both research focus. Autophagy is a highly controlled dynamic process, through which eukaryotic cells use lysosomes to degrade aging organelles and macromolecules substances (Klionsky, 2007; Lee et al, 2012; Levine & Klionsky, 2004). Several evidences suggest that phenotype transformation and autophagy play essential role in VC (Frauscher et al, 2018; Shroff & Shanahan, 2007). The molecular biological mechanisms are quite complicated and not fully understood

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