Protective role of cyclosporine A and minocycline on mitochondrial disequilibrium-related podocyte injury and proteinuria occurrence induced by adriamycin
Protective role of cyclosporine A and minocycline on mitochondrial disequilibrium-related podocyte injury and proteinuria occurrence induced by adriamycin
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环孢素A和米诺环素对阿霉素所致线粒体不平衡相关足细胞损伤和蛋白尿发生的保护作用
DOI：
10.1093/ndt/gfv015
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发表时间：
2015-06-01
影响因子：
6.1
通讯作者：
Fan, Qingfeng
中科院分区：
文献类型：
--
作者：
Guan, Na;Ren, Ya-Li;Fan, Qingfeng
背景资料。线粒体功能障碍与某些肾脏疾病的足细胞损伤有关，但线粒体形态异常与足细胞损伤的关系及其机制尚不清楚。本研究旨在研究阿霉素(ADR)诱导的足细胞损伤模型中线粒体形态的动态变化及潜在的分子事件。Annexin V法检测足细胞凋亡率。用MitoCapture试剂盒检测足细胞线粒体膜电位。用双染色法显示线粒体、肌动蛋白细丝、丝裂原蛋白和podocin的分布变化。用图像分析系统获取线粒体形状描述子。观察环孢素A(CsA)和米诺环素(Mcy)对阿霉素肾病大鼠肾脏线粒体形态的影响。ADR可引起足细胞损伤，表现为诱导细胞凋亡，激活的caspase3和细胞色素c增加，使足细胞基质金属蛋白酶水平明显降低。ADR引起的线粒体形态变化迅速，由大而椭圆形迅速向小、长、不规则方向发展。ADR显著降低线粒体的表面积、周长和圆周度，增加线粒体的长径比。此外，在应用ADR后6h，线粒体数量出现一过性增加。随着点状线粒体的形成，线粒体强度增加，点状线粒体与聚合的肌动蛋白细胞骨架共存于ADR足细胞。在ADR肾病大鼠中，CsA或Mcy可显著减少24 h蛋白尿。CsA或Mcy可恢复ADR所致的线粒体形态异常改变。CsA或Mcy.可明显减轻ADR大鼠肾小球中丝裂原蛋白的表达，减少肾小球中podocin的表达。线粒体功能障碍可能是ADR所致足细胞损伤的早期事件，CsA或Mcy的保护作用可能部分通过抑制丝裂原蛋白的诱导而改善线粒体功能。
Background. Dysfunction of mitochondria is involved in podocyte injury in some kidney diseases, but the relationship between abnormal mitochondrial morphology and podocyte injury as well as the underlying mechanism is still unclear. This study aims to investigate dynamic changes of mitochondrial morphology and the potential molecular events in an adriamycin (ADR)-induced podocyte injury model.Methods. Podocyte apoptosis was evaluated by annexin V assay. Podocyte mitochondrial membrane potential (MMP) was measured with MitoCapture kit. Double staining was used to show the distribution changes of mitochondria and actin filament as well as mitofusin proteins and podocin. Mitochondrial shape descriptors were obtained using analySIS Image system. Effects of cyclosporine A (CsA) or minocycline (Mcy) on mitochondrial morphology were explored in ADR-induced nephropathy rats.Results. ADR caused podocyte damage displaying as induction of cellular apoptosis and increase of activated caspase 3 and cytochrome c. The MMP level was decreased remarkably in ADR-treated podocytes. Mitochondrial morphological changes induced by ADR occurred rapidly from large and ellipsoid shape to the small, long and irregular. ADR significantly decreased surface area, perimeter and circularity, while increasing aspect ratio of mitochondria. In addition, mitochondria number transiently increased at 6 h following ADR application. Mitochondria intensity was increased along with punctate mitochondria formation, which co-localized with polymerized actin cytoskeleton in ADR podocytes. In ADR-induced nephropathy rats, 24-h proteinuria was decreased significantly by CsA or Mcy. ADR-induced abnormal changes of mitochondrial morphology were restored by CsA or Mcy. The induction of mitofusin proteins and the reduction of podocin in ADR rat glomeruli were rescued by CsA or Mcy.Conclusions. Mitochondrial dysfunction may be an early event in ADR-induced podocyte damage, and the protective role of CsA or Mcy may be mediated partially by improving mitochondrial function through inhibiting the induction of mitofusin proteins.