Yin Lei, Mao Youying, Song Hejie, Wang Ye, Zhou Wei, Zhang Zhen
Department of Nephrology and Rheumatology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China ; Pediatric Congenital Heart Disease Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Cell Biosci. 2017 Jan 3;7:1. doi: 10.1186/s13578-016-0129-z. eCollection 2017.
Antimicrotubule agent vincristine (VCR) has long been known as an alternative treatment for frequent relapse nephrotic syndrome and steroid-dependent nephrotic syndrome (SDNS). However, the mechanism is unknown. Here we found that VCR at a dosage much lower than that as an antimicrotubule agent can alleviate adriamycin (ADR)-induced proteinuria and podocyte foot process effacement. In cultured podocytes, VCR prevents ADR-induced actin fiber disorganization. In both in vitro and in vivo models, VCR suppresses ADR-induced overexpression of α3β1 integrin and focal adhesion kinase (FAK). These data suggest that VCR may relieve ADR-induced nephropathy through inhibiting injury-induced activation of integrin outside-in signaling to prevent actin cytoskeleton remodeling. Hence, our work reveals a novel role of VCR in regulating actin fiber assembly and provides first evidence on the therapeutic mechanism of VCR on nephrotic syndrome.
抗微管药物长春新碱（VCR）长期以来一直被用作频繁复发肾病综合征和激素依赖型肾病综合征（SDNS）的替代治疗方法。然而，其机制尚不清楚。在此我们发现，剂量远低于作为抗微管药物时的VCR可减轻阿霉素（ADR）诱导的蛋白尿和足细胞足突消失。在培养的足细胞中，VCR可防止ADR诱导的肌动蛋白纤维紊乱。在体外和体内模型中，VCR均抑制ADR诱导的α3β1整合素和粘着斑激酶（FAK）的过表达。这些数据表明，VCR可能通过抑制损伤诱导的整合素外向内信号激活来缓解ADR诱导的肾病，从而防止肌动蛋白细胞骨架重塑。因此，我们的工作揭示了VCR在调节肌动蛋白纤维组装中的新作用，并为VCR治疗肾病综合征的机制提供了首个证据。
