Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
J Leukoc Biol. 2022 Mar;111(3):553-562. doi: 10.1002/JLB.6A1020-699RRR. Epub 2021 Jun 1.
Diabetic nephropathy (DN) is a leading cause of end-stage renal failure. The study aimed to investigate whether long noncoding RNA taurine-upregulated gene 1 (TUG1) can ameliorate the endoplasmic reticulum stress (ERS) and apoptosis of renal tubular epithelial cells in DN, and the underlying mechanism. The DN mouse model was established by streptozocin injection, and the human renal tubular epithelial cell line HK-2 was treated with high glucose (HG) to mimic DN in vitro. The molecular mechanism was explored through dual-luciferase activity assay, RNA pull-down assay, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (CHIP) assay. The expression of TUG1 was significantly decreased in the renal tubules of DN model mice. Overexpression of TUG1 reduced the levels of ERS markers and apoptosis markers by inhibiting reticulon-1 (RTN1) expression in HG-induced HK-2 cells. Furthermore, TUG1 down-regulated RTN1 expression by inhibiting the binding of transcription factor PU.1 to the RTN1 promoter, thereby reducing the levels of ERS markers and apoptosis markers. Meanwhile, TUG1-overexpression adenovirus plasmids injection significantly alleviated tubular lesions, and reduced RTN1 expression, ERS markers and apoptosis markers, whereas these results were reversed by injection of PU.1-overexpression adenovirus plasmids. TUG1 restrains the ERS and apoptosis of renal tubular epithelial cells and ameliorates DN through inhibition of transcription factor PU.1.
糖尿病肾病（DN）是终末期肾衰竭的主要原因。本研究旨在探讨长链非编码 RNA 牛磺酸上调基因 1（TUG1）是否可以改善 DN 中肾小管上皮细胞的内质网应激（ERS）和细胞凋亡，以及潜在的机制。通过链脲佐菌素注射建立 DN 小鼠模型，并通过高糖（HG）处理人肾小管上皮细胞系 HK-2 来模拟体外 DN。通过双荧光素酶活性测定、RNA 下拉测定、RNA 免疫沉淀（RIP）和染色质免疫沉淀（CHIP）测定来探索分子机制。DN 模型小鼠肾小管中 TUG1 的表达明显降低。过表达 TUG1 通过抑制 RTN1 表达降低 HG 诱导的 HK-2 细胞中 ERS 标志物和凋亡标志物的水平。此外，TUG1 通过抑制转录因子 PU.1 与 RTN1 启动子的结合来下调 RTN1 表达，从而降低 ERS 标志物和凋亡标志物的水平。同时，TUG1 过表达腺病毒质粒注射显著减轻肾小管病变，并降低 RTN1 表达、ERS 标志物和凋亡标志物，而注射 PU.1 过表达腺病毒质粒则逆转了这些结果。TUG1 通过抑制转录因子 PU.1 来抑制肾小管上皮细胞的 ERS 和凋亡，从而改善 DN。
