title: TGFβ-Induced Actin Cytoskeleton Rearrangement in Podocytes Is Associated with Compensatory Adaptation of Mitochondrial Energy Metabolism.
abstract: OBJECTIVE
  In podocytes, the overexpression of TGFβ ligands and receptors during glomerulosclerosis could be a causal factor for injury induction and perpetuation in glomerular tufts. Mitochondrial dysfunction and oxidative stress are emerging as potential therapeutic targets in glomerular injury, and TGFβ has been shown to modulate mitochondrial metabolism in different cell types. This study aims at investigating the role of TGFβ in podocyte energy metabolism and cytoskeleton dynamics.
  
  
  METHODS
  Mitochondrial function and cytoskeleton dynamics were analyzed in TGFβ-treated WT and Smad2/3 double KO podocytes.
  
  
  RESULTS
  TGFβ treatment in podocytes induced a significant Smad-dependent increase of mitochondrial oxygen consumption rate (OCR). ATP content was unchanged and increased respiration was not associated with increased mitochondrial mass. Increased cellular reactive oxygen species induced by Smad-mediated TGFβ signaling were reverted by NADPH oxidase inhibitor apocynin. TGFβ treatment did not induce mitochondrial oxidative stress, and Smad2/3-dependent TGFβ signaling and increased mitochondrial OCR were found to be associated with actin cytoskeleton dynamics. The role of motor proteins myosin II and dynamin in TGFβ-induced actin polymerization was demonstrated by specific inhibition, resulting in actin stabilization and normalization of mitochondrial OCR.
  
  
  CONCLUSIONS
  TGFβ-induced rearrangements of actin cytoskeleton are controlled by Smad2/3 signaling pathways and coupled with the activation of mitochondrial ATP synthesis as bioenergetic adaptation to ATP consumption by ATP- and GTP-dependent motor proteins, myosin II and dynamin.
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, N.Y., USA.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Casalena
authors.forename: Erwin
authors.initials: E
authors.lastname: Bottinger
authors.forename: Ilse
authors.initials: I
authors.lastname: Daehn
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D000222:Adaptation, Physiological; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D000255:Adenosine Triphosphate