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- Title
t-PA promotes glomerular plasmin generation and matrix degradation in experimental glomerulonephritis.
- Authors
Haraguchi, Masashi; Border, Wayne A.; Huang, Yufeng; Noble, Nancy A.; Haraguchi, M; Border, W A; Huang, Y; Noble, N A
- Abstract
t-PA promotes glomerular plasmin generation and matrix degradation in experimental glomerulonephritis. Background. In addition to its well-known role in degrading fibrin, recent evidence suggests that plasmin degrades matrix proteins and activates prometalloproteinases. Plasmin is generated from plasminogen by tissue plasminogen activator (t-PA). We hypothesized that t-PA treatment increases plasmin generation in nephritic glomeruli and degrades pathological matrix leading to a therapeutic reduction in matrix accumulation. Methods. Anti–Thy-1 nephritis was induced by injection of OX-7 antibody. Rats were given twice daily intravenous injections of saline (disease control group) or human recombinant t-PA (rt-PA; 1 mg/kg body weight) on days 3 through 5. Proteinuria, glomerular matrix protein staining, and glomerular mRNA levels for transforming growth factor-β1 (TGF-β1), fibronectin, and plasminogen activator inhibitor type 1 (PAI-1) were evaluated at day 6. Localization of rt-PA, plasmin generation by glomeruli in vitro, and glomerular production and content of active TGF-β1 were also investigated. Results. Compared with disease control animals, proteinuria and staining score for periodic acid-Schiff (2.75 ± 0.17 vs. 1.41 ± 0.09), fibronectin-EDA+ (19 ± 2 vs. 14 ± 1), laminin (35 ± 2 vs. 25 ± 2), type I collagen (33 ± 1 vs. 21 ± 3), and type IV collagen (27 ± 2 vs. 23 ± 1) were significantly reduced in treated rats (P < 0.01). Glomerular TGF-β1, fibronectin, and PAI-1 mRNA levels were unchanged. rt-PA colocalized with fibrin along glomerular capillary walls and in the mesangium. Nephritic glomeruli in vitro had decreased plasmin activity, which was elevated by an in vivo presacrifice injection of rt-PA. Glomerular production and content of active TGF-β1 were unchanged by the rt-PA injection. Conclusions. These results show that injected rt-PA binds to fibrin in nephritic glomeruli, thus increasing plasmin generation and promoting pathological matrix degradation without activating latent TGF-β. Agents that increase plasmin generation, such as t-PA, may have potential as antifibrotic therapies.
- Subjects
TISSUE plasminogen activator; PLASMIN; GLOMERULONEPHRITIS; METALLOPROTEINASES; THERAPEUTICS
- Publication
Kidney International, 2001, Vol 59, Issue 6, p2146
- ISSN
0085-2538
- Publication type
journal article
- DOI
10.1046/j.1523-1755.2001.00729.x