PRMT3 通过甲基化 HIF-1α 增强慢性肾脏病引起的血管钙化。
PRMT3 methylates HIF-1α to enhance the vascular calcification induced by chronic kidney disease.
机构信息
Department of Nephrology, Shengjing Hospital of China Medical University, 36# Sanhao Street, Shenyang, China.
Department of Anesthesiology, Shengjing Hospital of China Medical University, 36# Sanhao Street, Shenyang, 110004, China.
出版信息
Mol Med. 2024 Jan 10;30(1):8. doi: 10.1186/s10020-023-00759-7.
BACKGROUND
Medial vascular calcification is commonly identified in chronic kidney disease (CKD) patients and seriously affects the health and life quality of patients. This study aimed to investigate the effects of protein arginine methyltransferase 3 (PRMT3) on vascular calcification induced by CKD.
METHODS
A mice model of CKD was established with a two-step diet containing high levels of calcium and phosphorus. Vascular smooth muscle cells (VSMCs) were subjected to β-glycerophosphate (β-GP) treatment to induce the osteogenic differentiation as an in vitro CKD model.
RESULTS
PRMT3 was upregulated in VSMCs of medial artery of CKD mice and β-GP-induced VSMCs. The inhibitor of PRMT3 (SGC707) alleviated the vascular calcification and inhibited the glycolysis of CKD mice. Knockdown of PRMT3 alleviated the β-GP-induced osteogenic transfomation of VSMCs by the repression of glycolysis. Next, PRMT3 interacted with hypoxia-induced factor 1α (HIF-1α), and the knockdown of PRMT3 downregulated the protein expression of HIF-1α by weakening its methylation. Gain of HIF-1α reversed the PRMT3 depletion-induced suppression of osteogenic differentiation and glycolysis of VSMCs.
CONCLUSION
The inhibitory role of PRMT3 depletion was at least mediated by the regulation of glycolysis upon repressing the methylation of HIF-1α.
背景
慢性肾脏病（CKD）患者常发生血管中层钙化，严重影响患者的健康和生活质量。本研究旨在探讨蛋白精氨酸甲基转移酶 3（PRMT3）对 CKD 诱导的血管钙化的影响。
方法
采用两步含高钙、高磷饮食法建立 CKD 小鼠模型。用β-甘油磷酸（β-GP）处理血管平滑肌细胞（VSMCs）以诱导成骨分化作为体外 CKD 模型。
结果
CKD 小鼠中动脉血管平滑肌细胞和β-GP 诱导的 VSMCs 中 PRMT3 上调。PRMT3 抑制剂（SGC707）减轻 CKD 小鼠的血管钙化并抑制其糖酵解。敲低 PRMT3 通过抑制糖酵解减轻β-GP 诱导的 VSMCs 成骨转化。接下来，PRMT3 与缺氧诱导因子 1α（HIF-1α）相互作用，敲低 PRMT3 通过减弱其甲基化来下调 HIF-1α 的蛋白表达。过表达 HIF-1α 逆转了 PRMT3 耗竭诱导的 VSMCs 成骨分化和糖酵解抑制作用。
结论
PRMT3 耗竭的抑制作用至少通过抑制 HIF-1α 的甲基化来调节糖酵解介导。
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