Renal Research Laboratory, Fondazione D'Amico per la Ricerca sulle Malattie Renali & Fondazione IRCCS Ca', Granda Ospedale Maggiore Policlinico, Milano, Italy.
J Pathol. 2015 Apr;235(5):731-44. doi: 10.1002/path.4484. Epub 2015 Jan 7.
Idiopathic focal segmental glomerulosclerosis (FSGS) is a progressive and proteinuric kidney disease that starts with podocyte injury. Podocytes cover the external side of the glomerular capillary by a complex web of primary and secondary ramifications. Similar to dendritic spines of neuronal cells, podocyte processes rely on a dynamic actin-based cytoskeletal architecture to maintain shape and function. Brain-derived neurotrophic factor (BDNF) is a pleiotropic neurotrophin that binds to the tropomyosin-related kinase B receptor (TrkB) and has crucial roles in neuron maturation, survival, and activity. In neuronal cultures, exogenously added BDNF increases the number and size of dendritic spines. In animal models, BDNF administration is beneficial in both central and peripheral nervous system disorders. Here we show that BDNF has a TrkB-dependent trophic activity on podocyte cell processes; by affecting microRNA-134 and microRNA-132 signalling, BDNF up-regulates Limk1 translation and phosphorylation, and increases cofilin phosphorylation, which results in actin polymerization. Importantly, BDNF effectively repairs podocyte damage in vitro, and contrasts proteinuria and glomerular lesions in in vivo models of FSGS, opening a potential new perspective to the treatment of podocyte disorders.
特发性局灶节段性肾小球硬化症（FSGS）是一种进行性、蛋白尿性肾脏疾病，起始于足细胞损伤。足细胞通过初级和次级分支的复杂网络覆盖肾小球毛细血管的外侧。与神经元细胞的树突棘相似，足细胞的突起依赖于一种动态的肌动蛋白细胞骨架架构来维持其形状和功能。脑源性神经营养因子（BDNF）是一种多效性神经营养因子，与原肌球蛋白相关激酶 B 受体（TrkB）结合，在神经元成熟、存活和活性中具有关键作用。在神经元培养物中，外源性添加的 BDNF 可增加树突棘的数量和大小。在动物模型中，BDNF 的给药对中枢和周围神经系统疾病都有益。在这里，我们表明 BDNF 对足细胞突起具有 TrkB 依赖性营养活性；通过影响 microRNA-134 和 microRNA-132 信号，BDNF 上调 Limk1 的翻译和磷酸化，并增加肌动蛋白丝解聚蛋白磷酸化，导致肌动蛋白聚合。重要的是，BDNF 可有效修复体外足细胞损伤，并在 FSGS 的体内模型中对比蛋白尿和肾小球病变，为治疗足细胞疾病提供了新的视角。
