Sclerostin is involved in osteogenic transdifferentiation of vascular smooth muscle cells in chronic kidney disease-associated vascular calcification with non-canonical Wnt signaling.
Sclerostin is involved in osteogenic transdifferentiation of vascular smooth muscle cells in chronic kidney disease-associated vascular calcification with non-canonical Wnt signaling.
复制标题
DOI：
10.1080/0886022x.2022.2114370
复制
发表时间：
2022-12
期刊：
影响因子：
3
通讯作者：
中科院分区：
文献类型：
--
作者：
血管钙化在慢性肾脏病（CKD）患者中很突出，是CKD人群心血管死亡率的强预测因子。然而，CKD相关血管钙化的机制仍不清楚。为了确定潜在的治疗靶点，通过喂养高磷饮食建立5/6肾切除大鼠模型作为CKD组，并在4周和16周与假手术组大鼠进行比较。大鼠主动脉的测序分析显示，与假手术组相比，CKD组在4周时有643个上调和1023个下调基因，在16周时有899个上调和1185个下调基因。生物信息学分析表明，SOST（编码硬化蛋白）和Wnt信号参与CKD相关的血管钙化。此外，蛋白质-蛋白质相互作用分析揭示了SOST、WNT 5A和WNT 5 B之间的相互作用，其涉及runt相关转录因子2（RUNX 2）和transgelin（TAGLN）。在体内和体外，在Wnt信号传导（包括WNT 5A和WNT 5 B）减少后，CKD相关血管钙化中的SOST增加。TargetScan用于预测靶向WNT 5A和WNT 5 B的microRNA（miRNAs）。在钙化的大鼠主动脉血管平滑肌细胞（VSMC）中，miR-542- 3 p、miR-298- 3 p、miR-376 b-5 p和miR-3568的表达水平显着降低，而miR-742- 3 p的表达水平显着增加。在CKD大鼠睾丸中，miR-542- 3 p、miR-298- 3 p、miR-376 b-5 p、miR-3568、miR-742- 3 p和miR-22- 5 p的表达在4周和16周均显著降低。总之，由于几项评估，本研究确定了用于改善常见CKD诊断工具的潜在诊断和预后生物标志物。 缩略语：我的天啊血尿素氮; CKD：慢性肾脏疾病; CKD-MBD：慢性肾病-矿物质骨疾病; GAPDH：甘油醛-3-磷酸脱氢酶; GO：基因本体论; HE：苏木精-伊红; HRP：辣根过氧化物酶; KEGG：京都基因和基因组百科全书; MiRNA：微小RNA; PAS：高碘酸-希夫; RUNX 2：runt相关转录因子2; SCr：血清肌酐; STRING：检索相互作用基因/蛋白质的搜索工具; TAGLN：transgelin; VSMC：血管平滑肌细胞
Vascular calcification is prominent in patients with chronic kidney disease (CKD) and is a strong predictor of cardiovascular mortality in the CKD population. However, the mechanism underlying CKD-associated vascular calcification remains unclear. To identify potential therapeutic targets, a 5/6 nephrectomy rat model was established by feeding of a high-phosphorous diet as the CKD group and compared with sham group rats at 4 and 16 weeks. Sequencing analyses of the rat aorta revealed 643 upregulated and 1023 downregulated genes at 4 weeks, as well as 899 upregulated and 1185 downregulated genes at 16 weeks in the CKD group compared to the sham group. Bioinformatics analyses suggested that SOST (which encodes sclerostin) and Wnt signaling are involved in CKD-associated vascular calcification. Furthermore, protein-protein interactions analysis revealed interactions between SOST, WNT5A, and WNT5B, that involved runt-related transcription factor 2 (RUNX2) and transgelin (TAGLN). SOST was increased in CKD-associated vascular calcification following reduction of the Wnt signaling, including WNT5A and WNT5B, both in vivo and in vitro. TargetScan was used to predict the microRNAs (miRNAs) targeting WNT5A and WNT5B. The expression levels of miR-542-3p, miR-298-3p, miR-376b-5p, and miR-3568 were significantly reduced, whereas that of miR-742-3p was significantly increased in calcified rat aortic vascular smooth muscle cells (VSMCs). In CKD rat aortas, the expression of miR-542-3p, miR-298-3p, miR-376b-5p, miR-3568, miR-742-3p, and miR-22-5p were significantly reduced at both 4 and 16 weeks. Altogether, owing to several assessments, potentially diagnostic and prognostic biomarkers for improving common CKD diagnostic tools were identified in this study. Abbreviations: BUN: blood urea nitrogen; CKD: chronic kidney disease; CKD-MBD: chronic kidney disease-mineral bone disorder; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GO: the Gene Ontology; HE: hematoxylin-eosin; HRP: horseradish peroxidase; KEGG: Kyoto Encyclopedia of Genes and Genomes; MiRNAs: microRNAs; PAS: periodic acid-Schiff; RUNX2: runt-related transcription factor 2; SCr: serum creatinine; STRING: the Search Tool for the Retrieval of Interacting Genes/Proteins; TAGLN: transgelin; VSMC: vascular smooth muscle cell.