Plectin protects podocytes from adriamycin-induced apoptosis and F-actin cytoskeletal disruption through the integrin α6β4/FAK/p38 MAPK pathway.
Plectin protects podocytes from adriamycin-induced apoptosis and F-actin cytoskeletal disruption through the integrin α6β4/FAK/p38 MAPK pathway.
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Plectin 通过整合素 α6β4/FAK/p38 MAPK 途径保护足细胞免受阿霉素诱导的细胞凋亡和 F-肌动蛋白细胞骨架破坏
DOI：
10.1111/jcmm.13816
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发表时间：
2018-11
影响因子：
5.3
通讯作者：
Zhao S
中科院分区：
文献类型：
--
作者：
Ni Y;Wang X;Yin X;Li Y;Liu X;Wang H;Liu X;Zhang J;Gao H;Shi B;Zhao S
足细胞损伤是多种肾小球疾病的早期病理改变特征，细胞凋亡和F -肌动蛋白细胞骨架破坏是足细胞损伤的典型特征。在这项研究中，我们发现阿霉素（ADR）治疗导致典型的足细胞损伤和抑制plectin表达。恢复plectin的表达可以防止ADR诱导的足细胞损伤，而siRNA介导的plectin沉默与ADR诱导的足细胞损伤效果相似，提示plectin在预防足细胞损伤中起关键作用。进一步分析发现，plectin的抑制诱导了显著的整合素α6β4、focal adhesion kinase （FAK）和p38 MAPK的磷酸化。突变整合素β4亚基中的关键酪氨酸残基Y1494，阻断FAK和p38磷酸化，从而减轻足细胞损伤。抑制剂研究表明，FAK Y397磷酸化促进p38活化，导致足细胞凋亡和F - actin细胞骨架破坏。体内研究表明，给大鼠施用ADR可显著提高24小时尿蛋白水平，降低凝集素表达，激活整合素α6β4、FAK和p38。综上所述，这些发现表明，plectin通过抑制整合素α6β4/FAK/p38通路的激活，保护足细胞免受ADR诱导的凋亡和F - actin细胞骨架破坏，并且plectin可能是足细胞损伤相关肾小球疾病的治疗靶点。
Podocyte injury is an early pathological change characteristic of various glomerular diseases, and apoptosis and F‐actin cytoskeletal disruption are typical features of podocyte injury. In this study, we found that adriamycin (ADR) treatment resulted in typical podocyte injury and repressed plectin expression. Restoring plectin expression protected against ADR‐induced podocyte injury whereas siRNA‐mediated plectin silencing produced similar effects as ADR‐induced podocyte injury, suggesting that plectin plays a key role in preventing podocyte injury. Further analysis showed that plectin repression induced significant integrin α6β4, focal adhesion kinase (FAK) and p38 MAPK phosphorylation. Mutating Y1494, a key tyrosine residue in the integrin β4 subunit, blocked FAK and p38 phosphorylation, thereby alleviating podocyte injury. Inhibitor studies demonstrated that FAK Y397 phosphorylation promoted p38 activation, resulting in podocyte apoptosis and F‐actin cytoskeletal disruption. In vivo studies showed that administration of ADR to rats resulted in significantly increased 24‐hour urine protein levels along with decreased plectin expression and activated integrin α6β4, FAK, and p38. Taken together, these findings indicated that plectin protects podocytes from ADR‐induced apoptosis and F‐actin cytoskeletal disruption by inhibiting integrin α6β4/FAK/p38 pathway activation and that plectin may be a therapeutic target for podocyte injury‐related glomerular diseases.
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