Tsai Yi-Chun, Kuo Po-Lin, Hung Wei-Wen, Wu Ling-Yu, Wu Ping-Hsun, Chang Wei-An, Kuo Mei-Chuan, Hsu Ya-Ling
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Mol Ther Nucleic Acids. 2018 Dec 7;13:543-555. doi: 10.1016/j.omtn.2018.10.003. Epub 2018 Oct 10.
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Mesangial cell (MC) loss is correlated with worsening renal function in DN. Disturbance of angiopoietin (Angpt)/Tie ligand-receptor system causes inflammation and abnormal angiogenesis. This association between elevated circulating Angpt2 and poor renal outcome has been in DN patients. However, the pathogenic role of Angpt2 in the MCs remains unknown. We found serum Angpt2 levels were elevated in type 2 diabetes mellitus (DM) patients and db/db mice, which correlated with albuminuria. Angpt2 synergistically induced MC apoptosis under high glucose (HG), and miR-33-5p regulated Angpt2-inducing MC apoptosis treated with HG. Loss of miR-33-5p increased suppressor of cytokine signaling 5 (SOCS5), leading to the inhibition of Janus kinase 1 and signal transducer and activator of transcription 3 signaling transduction. Elevated expression of SOCS5 was found in the MCs in kidney sections of both db/db mice and type 2 DM patients. Decreased miR-33-5p levels were found in the urine of db/db mice and type 2 DM patients, and miR-33-55p levels negatively correlated with albuminuria. Angpt2 leads to MC apoptosis via the miR-33-5p-SOCS5 loop in DN. miR-33-5p is predictive of kidney injury in DN. These findings may provide future applications in predicting renal dysfunction and the therapeutic potential of DN.
糖尿病肾病（DN）是终末期肾病的主要病因。系膜细胞（MC）丢失与DN患者肾功能恶化相关。血管生成素（Angpt）/Tie配体-受体系统紊乱会导致炎症和异常血管生成。循环中Angpt2升高与DN患者不良肾脏结局之间的这种关联已经得到证实。然而，Angpt2在MC中的致病作用仍不清楚。我们发现2型糖尿病（DM）患者和db/db小鼠血清Angpt2水平升高，且与蛋白尿相关。在高糖（HG）条件下，Angpt2协同诱导MC凋亡，而miR-33-5p调节HG处理后Angpt2诱导的MC凋亡。miR-33-5p缺失会增加细胞因子信号转导抑制因子5（SOCS5），导致Janus激酶1和信号转导及转录激活因子3信号转导受到抑制。在db/db小鼠和2型DM患者的肾组织切片的MC中均发现SOCS5表达升高。在db/db小鼠和2型DM患者的尿液中发现miR-33-5p水平降低，且miR-33-55p水平与蛋白尿呈负相关。在DN中，Angpt2通过miR-33-5p-SOCS5环导致MC凋亡。miR-33-5p可预测DN中的肾损伤。这些发现可能为预测肾功能障碍和DN的治疗潜力提供未来应用。
