Yuan Yanggang, Zhao Chuanyan, An Xiaofei, Wu Lin, Wang Hui, Zhao Min, Bai Mi, Duan Suyan, Zhang Bo, Zhang Aihua, Xing Changying
a Department of Nephrology , The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital , Nanjing , China ;
b Department of Endocrinology , Jiangsu Province Hospital of Chinese Medicine , Nanjing , China ;
Free Radic Res. 2016 Jun;50(6):627-37. doi: 10.3109/10715762.2016.1155706. Epub 2016 Mar 31.
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.
足细胞损伤是许多肾脏疾病的早期病理变化。特别是，肌动蛋白细胞骨架在维持足细胞的正常功能中起重要作用。肌动蛋白细胞骨架的破坏是蛋白尿性肾病中足细胞损伤的一个特征。最近的研究表明，肌球蛋白-9定位于足细胞足突中，对维持足细胞结构稳态是必需的。然而，尚不清楚肌球蛋白-9是否通过影响肌动蛋白细胞骨架来维持足细胞结构。在此，在体外和体内探索了肌球蛋白-9在嘌呤霉素氨基核苷（PAN）诱导的足细胞损伤中的作用。在培养的小鼠足细胞（MPC5）中，确定PAN下调肌球蛋白-9表达，破坏肌动蛋白细胞骨架并降低黏附能力。通过siRNA降低肌球蛋白-9表达加剧了足细胞细胞骨架损伤并加速了PAN诱导的足细胞脱离。肌球蛋白-9的过表达可防止PAN诱导的足细胞脱离。此外，给予抗氧化剂锰（III）四（4-苯甲酸）卟啉（MnTBAP）可通过恢复肌球蛋白-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还可减轻PAN诱导的肌球蛋白-9减少和足细胞丢失。综上所述，这些发现指出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，这为治疗与足细胞损伤相关的肾小球病的潜在靶点提供了新的见解。
