| First Author | Lassila M | Year | 2007 |
| Journal | Diabetologia | Volume | 50 |
| Issue | 6 | Pages | 1315-26 |
| PubMed ID | 17415547 | Mgi Jnum | J:141728 |
| Mgi Id | MGI:3819320 | Doi | 10.1007/s00125-007-0652-x |
| Citation | Lassila M, et al. (2007) Plasminogen activator inhibitor-1 production is pathogenetic in experimental murine diabetic renal disease. Diabetologia 50(6):1315-26 |
| abstractText | 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. |
