title: Plasminogen activator inhibitor-1 production is pathogenetic in experimental murine diabetic renal disease.
abstract: OBJECTIVE
  Plasminogen activator inhibitor-1 (PAI-1, also known as serpin peptidase inhibitor, clade E [nexin, plasminogen activator inhibitor type 1], member 1 [SERPINE1]) plays a pathogenetic role in renal fibrosis. It is upregulated in experimental and human diabetic nephropathy. These studies assessed the effect of PAI-1 deficiency and overproduction on renal disease in experimental diabetes.
  
  
  METHODS
  Diabetes was induced by injection of streptozotocin in 6-week-old PAI-1-deficient mice, transgenic mice overexpressing Pai-1 and control mice. Animals were killed after 24 weeks of diabetes or after observation alone.
  
  
  RESULTS
  Pai-1 mRNA was upregulated in kidneys from genetically normal mice with diabetes and in non-diabetic Pai-1 transgenic mice. PAI-1 was not further increased in kidneys from Pai-1 transgenic mice with diabetes. Diabetes-associated albuminuria and glomerular injury, as well as renal alpha-smooth muscle actin production, were ameliorated in diabetic PAI-1-deficient mice, an amelioration associated with attenuated increases in renal matrix metallopeptidase-2 expression and activity. Diabetic Pai-1 transgenic mice did not develop increased albuminuria or glomerular injury, but the tubulointerstitial area was modestly enhanced. In addition to the findings in diabetic mice, abnormalities also developed in 30-week-old PAI-1-deficient and Pai-1 transgenic mice without diabetes. PAI-1 deficiency resulted in increased tubulointerstitial area, TGFB1 protein and alpha-smooth muscle actin. Non-diabetic 30-week-old Pai-1 transgenic mice developed similar renal abnormalities and increased matrix metallopeptidase-2 activity, together with a modest increase in serum glucose and HbA(1c).
  
  
  CONCLUSIONS
  These results demonstrate that endogenous PAI-1 deficiency protects mice from glomerular injury in longer term diabetes and that endogenous PAI-1 maintains normal renal interstitial structure in ageing not associated with diabetes.
authors.affiliation: The Baker Heart Research Institute, Vascular Division, Danielle Alberti Memorial Centre for Diabetes Complications, Melbourne, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Lassila
authors.forename: K
authors.initials: K
authors.lastname: Fukami
authors.forename: K
authors.initials: K
authors.lastname: Jandeleit-Dahm
authors.forename: T
authors.initials: T
authors.lastname: Semple
authors.forename: P
authors.initials: P
authors.lastname: Carmeliet
authors.forename: M E
authors.initials: ME
authors.lastname: Cooper
authors.forename: A R
authors.initials: AR
authors.lastname: Kitching
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D012709:Serum Albumin