title: Calpains contribute to vascular repair in rapidly progressive form of glomerulonephritis: potential role of their externalization.
abstract: OBJECTIVE
  Calpains, calcium-activated proteases, mediate the angiogenic signals of vascular endothelial growth factor. However, their involvement in vascular repair has not been investigated and the underlying mechanisms remain to be fully elucidated.
  
  
  RESULTS
  A rapidly progressive form of glomerulonephritis in wild type and transgenic mice expressing high levels of calpastatin, a calpain-specific inhibitor, was studied. Calpastatin transgene expression prevented the repair of peritubular capillaries and the recovery of renal function, limiting mouse survival. In vitro analysis detected a significant reduction of both intracellular and extracellular calpain activities in transgene expressing cells, whereas Western blotting revealed that proangiogenic factors vascular endothelial growth factor and norepinephrine increased calpain exteriorization. In vitro, extracellular calpains increased endothelial cell proliferation, migration and capillary tube formation. In vivo, delivery of nonpermeable extracellular calpastatin was sufficient to blunt angiogenesis and vascular repair. Endothelial cell response to extracellular calpains was associated with fibronectin cleavage, generating fibronectin fragments with proangiogenic capacity. In vivo, fibronectin cleavage was limited in the kidney of calpastatin transgenic mice with nephritis.
  
  
  CONCLUSIONS
  This study demonstrates that externalized calpains participate in angiogenesis and vascular repair, partly by promoting fibronectin cleavage and thereby amplifying vascular endothelial growth factor efficiency. Thus, manipulation of calpain externalization may have therapeutic implications to control angiogenesis.
authors.affiliation: INSERM U702, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Letavernier
authors.forename: Lara
authors.initials: L
authors.lastname: Zafrani
authors.forename: Dany
authors.initials: D
authors.lastname: Nassar
authors.forename: Joëlle
authors.initials: J
authors.lastname: Perez
authors.forename: Charlène
authors.initials: C
authors.lastname: Levi
authors.forename: Agnès
authors.initials: A
authors.lastname: Bellocq
authors.forename: Laurent
authors.initials: L
authors.lastname: Mesnard
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Sachon
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Haymann
authors.forename: Selim
authors.initials: S
authors.lastname: Aractingi
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Faussat
authors.forename: Laurent
authors.initials: L
authors.lastname: Baud
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Letavernier
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000254:growth & development; D002154:Calpain / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D005921:Glomerulonephritis / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*
chemical_list: D005353:Fibronectins; D002154:Calpain