Guo Jing, Fu Rao, Zhao Bo, Li Hongbo, Jiao Jundong
Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China; Department of Nephrology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
Mol Cell Probes. 2025 Feb;79:102006. doi: 10.1016/j.mcp.2024.102006. Epub 2025 Jan 21.
Long non-coding RNA TMC3-AS1 is identified to be upregulated by lipopolysaccharide (LPS) in inflammatory disease, but its role in acute kidney injury (AKI) is almost unknown. The study investigated the involvement of TMC3-AS1 in LPS-induced AKI and its downstream molecular regulatory mechanism. Our data suggested that knocking down TMC3-AS1 significantly reduced renal dysfunction, tissue inflammation and tissue damage in LPS-induced mice, and promoted cell viability, inhibited inflammation, apoptosis and necrosis in LPS-stimulated human renal tubular epithelial cells HK2. Meanwhile, silencing TMC3-AS1 decreased the expression levels of Wnt5a, Atg5, NLRP3 and cleaved caspase1 and the ratio of LC3II/LC3I, but elevated p62 level in vivo and in vitro, suggesting the inhibitory effect of TMC3-AS1 silence on Wnt5a signaling, autophagy, and pyroptosis. Mechanically, TMC3-AS1 upregulated the expression of WNT5A mRNA and Wnt5a protein through competitively binding with miR-148a-3p, thus elevating the expression levels of autophagy and pyroptosis-associated markers in LPS-induced HK2 cells. MiR-148a-3p mimic also exerted protective effects on LPS-treated HK2 cells, which was counteracted by overexpressing WNT5A or TMC3-AS1. Altogether, these findings reveal that TMC3-AS1 inhibition restrains LPS-triggered AKI progression through inactivating Wnt5a -mediated autophagy and pyroptosis pathway.
长链非编码RNA TMC3-AS1在炎症性疾病中被脂多糖（LPS）上调，但它在急性肾损伤（AKI）中的作用几乎未知。本研究调查了TMC3-AS1在LPS诱导的AKI中的作用及其下游分子调控机制。我们的数据表明，敲低TMC3-AS1可显著降低LPS诱导小鼠的肾功能障碍、组织炎症和组织损伤，并促进LPS刺激的人肾小管上皮细胞HK2的细胞活力，抑制炎症、凋亡和坏死。同时，沉默TMC3-AS1可降低体内和体外Wnt5a、Atg5、NLRP3和裂解的caspase1的表达水平以及LC3II/LC3I的比率，但提高p62水平，表明沉默TMC3-AS1对Wnt5a信号通路、自噬和焦亡具有抑制作用。机制上，TMC3-AS1通过与miR-148a-3p竞争性结合上调WNT5A mRNA和Wnt5a蛋白的表达，从而提高LPS诱导的HK2细胞中自噬和焦亡相关标志物的表达水平。miR-148a-3p模拟物对LPS处理的HK2细胞也有保护作用，而过表达WNT5A或TMC3-AS1可抵消这种作用。总之，这些发现表明，抑制TMC3-AS1可通过失活Wnt5a介导的自噬和焦亡途径抑制LPS触发的AKI进展。
