肾小管上皮细胞衰老加速IgA肾病进展的作用机制研究

Cellular senescence has attracted significant attention due to its critical role in the fibrosis. Senescent cells demonstrate increased sensitivity to injury and decreased repair following injury. Tubulointerstitial fibrosis（TIF）plays a important role in IgAN progression, however, the molecular mechanism is unclear. Our previous studies have demonstrated cellular senescence of RTECs was associated closely with IgAN progression, suggesting that the accelerated senescence may contribute to IgAN progression. On the basis, we further explore the mechanism of cellular senescence promoting the development of IgAN by triggering TGF-β activation，EMT and ECM accumulation, which accelerated TIF progression. These findings may provide novel insight into the mechanism of TIF in IgAN, suggesting new therapeutic targets for the prevention of renal damage in IgAN.

细胞衰老与器官纤维化紧密关联，交互影响，协同促进疾病状态下的组织结构损伤和器管功能障碍。肾小管间质纤维化在IgAN进展至慢性肾衰竭中起到十分关键的主导作用，本课题在前期证实肾小管上皮细胞衰老与IgAN肾小管间质纤维化显著关联的基础上，采用动物模型与细胞实验相结合，利用基因过表达和基因沉默技术对细胞衰老的主控基因p16正负调控，围绕TGFβ1激活的纤维化关键环节，从EMT和肾间质ECM积聚的角度，全面深入解析肾小管上皮细胞衰老加速IgAN肾小管间质纤维化的分子机制。本课题率先揭示了肾小管上皮细胞衰老促进IgAN肾小管间质纤维化的病理生理机制，突破临床救治IgAN的传统思维，从抗细胞衰老角度为遏制IgAN进展提供新的科学思路和干预靶点。

细胞衰老与器官纤维化紧密关联，交互影响，协同促进疾病状态下的组织结构损伤和器管功能障碍。肾小管间质纤维化在IgAN进展至慢性肾衰竭中起到十分关键的主导作用，本课题在前期证实肾小管上皮细胞衰老与IgAN肾小管间质纤维化显著关联的基础上，利用基因过表达和基因沉默技术对细胞衰老的主控基因p16正负调控，围绕TGFβ1激活的纤维化关键环节，全面深入解析肾小管上皮细胞衰老加速IgAN肾小管间质纤维化的分子机制。研究结果显示：1）pIgA-HMC培养液可导致肾小管上皮细胞早衰；2）IgA-HMC培养液诱导的早衰肾小管上皮细胞产生细胞基质增加（TGF-β、FN、ColⅢ表达增加），参与IgAN肾间质纤维化的发生发展；3）p16 siRNA可以减轻IgA-HMC培养液诱导的肾小管上皮细胞早衰和细胞外基质增加；4）p16过表达可促进IgA-HMC培养液诱导的肾小管上皮细胞早衰和细胞外基质增加；5）p16过表达可直接诱导肾小管上皮细胞早衰和细胞外基质表达。6）TGF-β siRNA可以减轻p16过表达直接引起的肾小管上皮细胞早衰和细胞外基质增加。研究结果表明，p16介导的肾小管上皮细胞早衰通过诱导细胞外基质增加而加速IgA肾病进展，其中TGF-β激活对IgAN肾小管上皮细胞早衰和ECM积聚具有反馈性调控作用。本课题率先揭示了肾小管上皮细胞衰老促进IgAN肾小管间质纤维化的病理生理机制，突破临床救治IgAN的传统思维，从抗细胞衰老角度为遏制IgAN进展提供新的科学思路和干预靶点。