AIMS/HYPOTHESIS: 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. MATERIALS AND 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/ INTERPRETATION: 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.
AIMS/HYPOTHESIS: 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 humandiabetic nephropathy. These studies assessed the effect of PAI-1 deficiency and overproduction on renal disease in experimental diabetes. MATERIALS AND 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-diabeticPai-1transgenic mice. PAI-1 was not further increased in kidneys from Pai-1transgenic mice with diabetes. Diabetes-associated albuminuria and glomerular injury, as well as renal alpha-smooth muscle actin production, were ameliorated in diabetic PAI-1-deficientmice, an amelioration associated with attenuated increases in renal matrix metallopeptidase-2 expression and activity. DiabeticPai-1transgenic mice did not develop increased albuminuria or glomerular injury, but the tubulointerstitial area was modestly enhanced. In addition to the findings in diabeticmice, abnormalities also developed in 30-week-old PAI-1-deficient and Pai-1transgenic mice without diabetes. PAI-1 deficiency resulted in increased tubulointerstitial area, TGFB1 protein and alpha-smooth muscle actin. Non-diabetic 30-week-old Pai-1transgenic mice developed similar renal abnormalities and increased matrix metallopeptidase-2 activity, together with a modest increase in serum glucose and HbA(1c). CONCLUSIONS/ INTERPRETATION: 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: Li-Jun Ma; Su-Li Mao; Kevin L Taylor; Talerngsak Kanjanabuch; YouFei Guan; YaHua Zhang; Nancy J Brown; Larry L Swift; Owen P McGuinness; David H Wasserman; Douglas E Vaughan; Agnes B Fogo Journal: Diabetes Date: 2004-02 Impact factor: 9.461
Authors: G C Liu; F Fang; J Zhou; K Koulajian; S Yang; L Lam; H N Reich; R John; A M Herzenberg; A Giacca; G Y Oudit; J W Scholey Journal: Diabetologia Date: 2012-06-01 Impact factor: 10.122
Authors: Meriem Khairoun; Mieke van den Heuvel; Bernard M van den Berg; Oana Sorop; Rients de Boer; Nienke S van Ditzhuijzen; Ingeborg M Bajema; Hans J Baelde; Malu Zandbergen; Dirk J Duncker; Ton J Rabelink; Marlies E J Reinders; Wim J van der Giessen; Joris I Rotmans Journal: PLoS One Date: 2015-04-24 Impact factor: 3.240