LncRNA SOX2OT抑制糖尿病肾病系膜细胞基质分泌的机制研究

Long non-coding RNA (lncRNA) is a class of recently discovered molecules with important physiological functions in diabetic nephropathy (DN). However, the key lncRNA in mesangial matrix secretion is still unclear. Our preliminary microarray analysis and patient sample data showed that SOX2OT was the significantly down-regulated lncRNA in renal cortex of DN. Oxidative stress-induced change in transcription factor FoxO3a was showed to be the upstream regulator of SOX2OT gene expression. What’s more, the SOX2OT-regulated mesangial matrix secretion might be mediated by Wnt/β-catenin signaling pathway. Based on the above results, we propose the hypothesis: in mesangial cells of DN, oxidative stress attenuates FoxO3a activity and subsequently decreases SOX2OT expression. Then Wnt/β-catenin pathway is activated and followed by mesangial matrix over-secretion. Our study will use patient sample, animal model and cultured mesangial cells to explore: 1. Role and molecular mechanism of SOX2OT in mesangial matrix secretion of DN. 2. Upstream mechanism of SOX2OT expression. 3. Clinical application of SOX2OT in diagnosis and prognosis of DN. Our study may provide new ideas and targets for the diagnosis and treatment of DN.

长链非编码RNA（lncRNA）是新近发现的在糖尿病肾病（DN）中具有重要生理功能的一类分子，但系膜细胞基质分泌中的关键lncRNA尚未明确。我们通过基因芯片筛选及患者标本验证发现SOX2OT是DN肾皮质中表达显著降低的lncRNA。预实验发现氧化应激导致的转录因子FoxO3a活性改变是影响SOX2OT表达的上游因素，且SOX2OT可能通过Wnt/β-catenin通路对系膜细胞基质分泌产生重要调控作用。因此我们提出假设：DN中系膜细胞氧化应激抑制FoxO3a活性，SOX2OT表达降低并活化Wnt/β-catenin通路，系膜细胞基质过度分泌。课题拟通过患者标本、动物模型及体外培养的系膜细胞观察：1.SOX2OT在DN系膜细胞基质分泌中的作用及分子机制；2.SOX2OT表达失控的上游机制；3.SOX2OT在DN诊断及预后分析中的应用价值。通过上述研究有望为DN的诊治提供新的思路及靶点。

糖尿病肾病 (diabetic nephropathy, DN) 作为糖尿病 (diabetes mellitus, DM) 的主要微血管并发症，已成为世界范围内肾功能衰竭的主要原因。长链非编码RNA (Long non-coding RNA, LncRNA)在多种细胞反应、发育和疾病过程中发挥着重要作用。前期研究表明lncRNA SOX2OT (Sox2 overlapping transcript) 在DN肾皮质中表达显著降低，而氧化应激导致的转录因子FoxO3a活性改变是影响SOX2OT表达的上游因素，且SOX2OT可能通过Wnt/β-catenin通路对系膜细胞基质分泌产生重要调控作用。我们提出以下科学假设：DN 时氧化应激引起系膜细胞 FoxO3a 活性下降，SOX2OT 表达降低，从而解除对 Wnt/β-catenin 通路的抑制作用，引起基质分泌亢进。我们的研究发现：1. 高糖诱导氧化应激对人肾小球系膜细胞中lncRNA SOX2OT及基质蛋白的表达变化。 2. 氧化应激通过转录因子FoxO3a调控lncRNA SOX2OT的表达。3. lncRNA SOX2OT通过Wnt/β-catenin通路调控系膜细胞基质分泌。上述研究成果验证了我们的科学假设，并表明干预lncRNA SOX2OT可缓解糖尿病肾病引起的系膜细胞基质过度分泌及肾脏纤维化进展，有望为糖尿病肾病的早期诊断和治疗提供新的思路和靶点。有望为探索糖尿病肾病治疗的新靶点提供依据。