title: Protective role of cyclosporine A and minocycline on mitochondrial disequilibrium-related podocyte injury and proteinuria occurrence induced by adriamycin.
abstract: 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.
authors: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
authors: Na
authors: N
authors: Guan
authors: Department of Electron Microscopy, Peking University First Hospital, Beijing 100034, China.
authors: Ya-Li
authors: YL
authors: Ren
authors: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
authors: Xiao-Ya
authors: XY
authors: Liu
authors: Department of Central Laboratory, Peking University First Hospital, Beijing 100034, China.
authors: Ying
authors: Y
authors: Zhang
authors: Department of Central Laboratory, Peking University First Hospital, Beijing 100034, China.
authors: Pei
authors: P
authors: Pei
authors: Department of Biostatistics, Peking University First Hospital, Beijing 100034, China.
authors: Sai-Nan
authors: SN
authors: Zhu
authors: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China Present address: Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Qingfeng
authors: Q
authors: Fan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004317:Doxorubicin / Q000633:toxicity*; D005455:Fluorescent Antibody Technique; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008911:Minocycline / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D004317:Doxorubicin; D016572:Cyclosporine; D053148:Caspase 3; D008911:Minocycline
keywords: cyclosporine A; minocycline; mitochondria; mitofusin; podocyte