A vital role for myosin-9 in puromycin aminonucleoside-induced podocyte injury by affecting actin cytoskeleton
A vital role for myosin-9 in puromycin aminonucleoside-induced podocyte injury by affecting actin cytoskeleton
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DOI：
10.3109/10715762.2016.1155706
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发表时间：
2016-03
影响因子：
3.3
通讯作者：
Yanggang Yuan;Chuanyan Zhao;Xiaofei An;Lin Wu;Hui Wang;Min Zhao;M. Bai;S. Duan;Bo Zhang
中科院分区：
文献类型：
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作者：
Yanggang Yuan;Chuanyan Zhao;Xiaofei An;Lin Wu;Hui Wang;Min Zhao;M. Bai;S. Duan;Bo Zhang
足细胞损伤是多种肾脏疾病的早期病理改变。特别是肌动蛋白细胞骨架在维持足细胞的正常功能方面起着重要作用。肌动蛋白细胞骨架的破坏是蛋白尿肾病足细胞损伤的一个特征。最近的研究表明，肌球蛋白-9定位于足细胞足突，是维持足细胞结构稳态所必需的。然而，肌球蛋白-9是否通过影响肌动蛋白细胞骨架来维持足细胞结构尚不清楚。本研究通过体外和体内实验，探讨了肌球蛋白-9在嘌呤霉素氨基核苷（PAN）诱导足细胞损伤中的作用。在培养的小鼠足细胞（MPC5）中，测定了PAN下调myosin-9的表达，破坏肌动蛋白细胞骨架，降低粘附能力。通过siRNA降低myosin-9的表达可导致足细胞骨架损伤，加速pan诱导的足细胞脱离。肌球蛋白-9的过表达对pan诱导的足细胞脱离有保护作用。此外，抗氧化剂锰（III）四苯甲酸卟啉（MnTBAP）通过恢复肌球蛋白-9的表达来抑制pan诱导的足细胞细胞骨架损伤和足细胞脱离。在大鼠PAN肾病模型中，MnTBAP还能减弱PAN诱导的肌球蛋白-9减少和足细胞损失。综上所述，这些发现明确了氧化应激通过抑制细胞骨架蛋白肌球蛋白-9导致pan诱导的足细胞损伤，这为治疗足细胞损伤相关肾小球疾病的潜在靶点提供了新的见解。
ABSTRACT Podocyte injury is an early pathological change of many kidney diseases. In particular, the actin cytoskeleton plays an important role in maintaining the normal function of podocytes. Disruption of the actin cytoskeleton is a feature of podocyte injury in proteinuric nephropathies. Recent studies showed that myosin-9 was localized in the podocyte foot processes and was necessary in maintaining podocyte structural homeostasis. However, it is unclear whether myosin-9 maintains podocyte structure by affecting actin cytoskleton. Here, the role of myosin-9 in puromycin aminonucleoside (PAN)-induced podocyte injury was explored both in vitro and in vivo. In cultured mouse podocytes (MPC5), it was determined that PAN downregulated myosin-9 expression, disrupted the actin cytoskeleton and reduced the adhesion ability. Reduced myosin-9 expression by siRNA precipitated podocyte cytoskeletal damage and accelerated PAN-induced podocyte detachment. Overexpression of myosin-9 protected against PAN-induced podocyte detachment. Furthermore, administration of an antioxidant Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP) inhibited PAN-induced podocyte cytoskeletal damage and podocyte detachment by restoring the expression of myosin-9. In the rat PAN nephropathy model, MnTBAP could also attenuate PAN-induced reduction of myosin-9 and podocyte loss. Taken together, these findings pinpointed that oxidative stress contributed to PAN-induced podocyte injury through the repression of a cytoskeletal protein myosin-9, which provided novel insights into a potential target for the treatment of podocyte injury-associated glomerulopathies.