Department of Nephrology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, PR China.
Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, PR China.
Ren Fail. 2022 Dec;44(1):1426-1442. doi: 10.1080/0886022X.2022.2114370.
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 (which encodes sclerostin) and Wnt signaling are involved in CKD-associated vascular calcification. Furthermore, protein-protein interactions analysis revealed interactions between , , and , that involved runt-related transcription factor 2 () and transgelin (). was increased in CKD-associated vascular calcification following reduction of the Wnt signaling, including and , both and . TargetScan was used to predict the microRNAs (miRNAs) targeting and . 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. 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.
血管钙化在慢性肾脏病（CKD）患者中很明显，是 CKD 人群心血管死亡率的有力预测因子。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，通过给予高磷饮食建立了 5/6 肾切除术大鼠模型作为 CKD 组，并在 4 周和 16 周时与假手术组大鼠进行比较。对大鼠主动脉的测序分析显示，与假手术组相比，CKD 组在 4 周时上调了 643 个基因，下调了 1023 个基因，在 16 周时上调了 899 个基因，下调了 1185 个基因。生物信息学分析表明，骨硬化蛋白（SOST）基因编码的骨硬化蛋白和 Wnt 信号通路参与 CKD 相关血管钙化。此外，蛋白质-蛋白质相互作用分析显示，SOST 与 runt 相关转录因子 2（RUNX2）和转胶蛋白（TAGLN）之间存在相互作用。在 Wnt 信号通路被抑制后，CKD 相关血管钙化中 表达增加，包括 SOST 和 Wnt 信号通路的下游分子骨桥蛋白（OPN）和骨涎蛋白（BSP）。靶向预测显示，SOST 可能靶向 miR-542-3p、miR-298-3p、miR-376b-5p 和 miR-3568。在钙化的大鼠主动脉血管平滑肌细胞（VSMCs）中，miR-542-3p、miR-298-3p、miR-376b-5p 和 miR-3568 的表达水平显著降低，而 miR-742-3p 的表达水平显著升高。在 CKD 大鼠主动脉中，miR-542-3p、miR-298-3p、miR-376b-5p、miR-3568、miR-742-3p 和 miR-22-5p 的表达在 4 周和 16 周时均显著降低。总之，通过多种评估，本研究确定了改善常见 CKD 诊断工具的潜在诊断和预后生物标志物。BUN：血尿素氮；CKD：慢性肾脏病；CKD-MBD：慢性肾脏病-矿物质和骨代谢紊乱；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：京都基因与基因组百科全书；miRNAs：microRNAs；PAS：过碘酸-希夫；RUNX2：runt 相关转录因子 2；SCr：血清肌酐；STRING：检索相互作用基因/蛋白质的工具；TAGLN：转胶蛋白；VSMC：血管平滑肌细胞。
