整合素β1/FAK促进梗阻性肾病肾间质纤维化过程的机制研究

Integrin participates in different pathophysiological processes caused by mechanical stretch. The binding of focal adhesion .kinase (FAK) and integrin β1 subunit and intracellular signal transduction, which is mediated by extracellular mechanical stretch, participate in regulating cell cycle, differentiation, adhesion, migration and other processes. FAK plays an important role in the process of fibrosis of different diseases, but its role in renal interstitial fibrosis is rarely studied at home and abroad. Recent studies have shown that FAK mediates epithelial mesenchymal transformation (EMT) in different cells. Our previous studies have shown that FAK is highly expressed in obstructive kidneys and models, and FAK is involved in the EMT of tubular epithelial cells and the activation of fibroblasts. Thus we suggest that integrin β1 / FAK can mediate renal tubular epithelial cells’partial EMT and fibroblasts activation via mechanical stretch..This study aims to elucidate the function and mechanism of integrin β1 / FAK in obstructive nephropathy, and to further explore the molecular mechanism and involving pathways of EMT and fibroblasts’activation in renal tubular epithelial cells by gene chip and other techniques. We aimed to identify the key molecules in renal interstitial fibrosis caused by mechanical stretch for the clinical diagnosis and treatment , find the new targets for obstructive nephropathy renal fibrosis targeting therapy.

整合素参与机械牵张所致的不同病理生理过程。黏着斑激酶FAK与整合素的β1亚基结合介导细胞外机械牵张引起的胞内信号转导，参与调节细胞的细胞周期、分化、粘附、迁移等过程。FAK在不同疾病的纤维化过程中起到重要作用，但其在肾间质纤维化中的作用国内外还鲜有研究。近年来的研究显示FAK在不同细胞中介导上皮间质转化EMT。我们的前期研究表明FAK在梗阻肾及模型中高表达，且FAK参与机械牵张刺激下肾小管上皮细胞EMT和成纤维细胞激活。由此我们提出整合素β1/FAK可介导机械牵张引起肾小管上皮细胞部分EMT和成纤维细胞激活导致肾间质纤维化。本项目拟阐述整合素β1/FAK在梗阻性肾病中的作用及机制，并进一步通过基因芯片等技术查明其介导机械牵张引起肾小管上皮细胞EMT及成纤维细胞激活的下游分子机制和相关通路。寻找机械牵张引起肾间质纤维化的关键的分子，为临床诊疗提供分子标志物，发现梗阻性肾病肾纤维化治疗新靶点。

整合素参与机械牵张所致的不同病理生理过程。黏着斑激酶FAK与整合素的β1亚基结合介导细胞外机械牵张引起的胞内信号转导，参与调节细胞的细胞周期、分化、粘附、迁移等过程。FAK在不同疾病的纤维化过程中起到重要作用，但其在肾间质纤维化中的作用国内外还鲜有研究。近年来的研究显示FAK在不同细胞中介导上皮间质转化EMT。本研究从梗阻性肾纤维化发病机制出发，聚焦整合素 β1、FAK、肾小管上皮细胞EMT、成纤维细胞激活及相关信号通路、肾纤维药物治疗展开研究。结果发现磷酸化FAK在梗阻性肾病肾间质纤维化中表达升高，FAK可能在梗阻性肾病肾间质纤维化过程中发挥促进作用，并可能作为整合素β1 的下游，通过促进肌成纤维细胞而发挥作用。我们发现MALAT1/miR-145/FAK通路，PTEN/FAK/AKT通路参与肾纤维化发生发展，长链非编码 RNA MIAT调节肾间质纤维化的EMT。此外我们发现了药物双氢青蒿素和姜黄素可以通过不同机制来减轻肾间质纤维化。以上发现揭示了肾间质纤维化的关键的分子和信号通路，发掘了抗肾纤维化的新型药物，为梗阻性肾病肾纤维化治疗提供了新靶点和新的方向。