Data_Sheet_2_Integrin β3 Induction Promotes Tubular Cell Senescence and Kidney Fibrosis.XLS

Tubular cell senescence is a common biologic process and contributes to the progression of chronic kidney disease (CKD); however, the molecular mechanisms regulating tubular cell senescence are poorly understood. Here, we report that integrin β3 (ITGB3) expression was increased in tubular cells and positively correlated with fibrosis degree in CKD patients. ITGB3 overexpression could induce p53 pathway activation and the secretion of TGF-β, which, in turn, resulted in senescent and profibrotic phenotype change in cultured tubular cells. Moreover, according to the CMAP database, we identified isoliquiritigenin (ISL) as an agent to inhibit ITGB3. ISL treatment could suppress Itgb3 expression, attenuate cellular senescence, and prevent renal fibrosis in mice. These results reveal a crucial role for integrin signaling in cellular senescence, potentially identifying a new therapeutic direction for kidney fibrosis.

肾小管细胞衰老（tubular cell senescence）是一种常见的生物学过程，可促进慢性肾脏病（chronic kidney disease, CKD）的进展；然而，调控肾小管细胞衰老的分子机制目前仍不甚明确。本研究发现，整合素β3（integrin β3, ITGB3）在肾小管细胞中的表达水平显著升高，且与CKD患者的肾脏纤维化程度呈正相关。过表达ITGB3可诱导p53信号通路（p53 pathway）激活以及转化生长因子-β（transforming growth factor-β, TGF-β）的分泌，进而使体外培养的肾小管细胞出现衰老及促纤维化表型改变。此外，通过连接性图谱（Connectivity Map, CMAP）数据库，我们鉴定出异甘草素（isoliquiritigenin, ISL）可作为抑制ITGB3的活性化合物。在小鼠模型中，异甘草素（ISL）处理可抑制Itgb3的表达，减轻细胞衰老，并延缓肾脏纤维化的进展。本研究结果揭示了整合素信号通路（integrin signaling）在细胞衰老中的关键作用，为肾脏纤维化的治疗提供了全新的潜在方向。