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Plasminogen and plasminogen activators protect against renal injury in crescentic glomerulonephritis.

Kitching AR, Holdsworth SR, Ploplis VA, Plow EF, Collen D, Carmeliet P, Tipping PG - J. Exp. Med. (1997)

Bottom Line: The plasminogen/plasmin system has the potential to affect the outcome of inflammatory diseases by regulating accumulation of fibrin and other matrix proteins.Deficiency of tPA, the predominant plasminogen activator expressed in glomeruli, also exacerbated disease. uPA deficiency reduced glomerular macrophage infiltration and did not significantly exacerbate disease. uPA receptor deficiency did not effect the expression of GN.These studies demonstrate that plasminogen plays an important role in protecting the glomerulus from acute inflammatory injury and that tPA is the major protective plasminogen activator.

View Article: PubMed Central - PubMed

Affiliation: Center for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Victoria, Australia.

ABSTRACT
The plasminogen/plasmin system has the potential to affect the outcome of inflammatory diseases by regulating accumulation of fibrin and other matrix proteins. In human and experimental crescentic glomerulonephritis (GN), fibrin is an important mediator of glomerular injury and renal impairment. Glomerular deposition of matrix proteins is a feature of progressive disease. To study the role of plasminogen and plasminogen activators in the development of inflammatory glomerular injury, GN was induced in mice in which the genes for these proteins had been disrupted by homologous recombination. Deficiency of plasminogen or combined deficiency of tissue type plasminogen activator (tPA) and urokinase type plasminogen activator (uPA) was associated with severe functional and histological exacerbation of glomerular injury. Deficiency of tPA, the predominant plasminogen activator expressed in glomeruli, also exacerbated disease. uPA deficiency reduced glomerular macrophage infiltration and did not significantly exacerbate disease. uPA receptor deficiency did not effect the expression of GN. These studies demonstrate that plasminogen plays an important role in protecting the glomerulus from acute inflammatory injury and that tPA is the major protective plasminogen activator.

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Photomicrographs  of representative glomeruli from  WT mice (A and B, Plg-deficient mice (C and D) and combined tPA- and uPA-deficient  mice (E and F) with GN demonstrating light microscopic appearances (PAS stain, magnification ×350) and fibrin deposition  (immunofluorescence, magnification ×400). WT mice with  GN at day 10 showed proliferative GN (A) and segmental fibrin  deposition within the glomerular  tuft (B). Plg-deficient mice at day  8 developed hypocellular glomeruli with extensive deposition  of PAS+ material in the glomerular tuft and cellular crescent formation (C, arrowed) and extensive  fibrin deposition within the glomerular tuft and in Bowman's  space (D, arrowed). Mice with  combined tPA, uPA deficiency at  day 10 showed similar histological features to Plg-deficient mice  (E) and similar extensive glomerular fibrin deposition (F).
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Figure 1: Photomicrographs of representative glomeruli from WT mice (A and B, Plg-deficient mice (C and D) and combined tPA- and uPA-deficient mice (E and F) with GN demonstrating light microscopic appearances (PAS stain, magnification ×350) and fibrin deposition (immunofluorescence, magnification ×400). WT mice with GN at day 10 showed proliferative GN (A) and segmental fibrin deposition within the glomerular tuft (B). Plg-deficient mice at day 8 developed hypocellular glomeruli with extensive deposition of PAS+ material in the glomerular tuft and cellular crescent formation (C, arrowed) and extensive fibrin deposition within the glomerular tuft and in Bowman's space (D, arrowed). Mice with combined tPA, uPA deficiency at day 10 showed similar histological features to Plg-deficient mice (E) and similar extensive glomerular fibrin deposition (F).

Mentions: All WT mice developed proliferative GN (Fig. 1 A) with occasional glomeruli exhibiting crescent formation. Areas of basement membrane thickening were demonstrated by silver methenamine staining (not shown) and segmental fibrin deposition was observed within the glomerular tuft by direct immunofluorescence (Fig. 1 B). Glomeruli of both Plg−/− and tPA−/−:uPA−/− mice were more severely affected, with tuft necrosis and relatively hypocellular glomeruli (Fig. 1, C and E). Despite this relative hypocellularity, there were more macrophages within glomeruli and significantly increased numbers of glomeruli exhibiting crescent formation compared to their respective WT controls (Table 1). Crescents in the Plg−/− and tPA−/−: uPA−/− animals were larger than those found in WT mice and contained both cellular elements (Fig. 1, C and E, arrowed), and fibrin (Fig. 1, D and F, arrowed). Deposition of PAS+ material within glomeruli was significantly increased (Table 1) indicating more extra cellular matrix deposition in nephritic Plg−/− and tPA−/−:uPA−/− mice, compared to WT animals.


Plasminogen and plasminogen activators protect against renal injury in crescentic glomerulonephritis.

Kitching AR, Holdsworth SR, Ploplis VA, Plow EF, Collen D, Carmeliet P, Tipping PG - J. Exp. Med. (1997)

Photomicrographs  of representative glomeruli from  WT mice (A and B, Plg-deficient mice (C and D) and combined tPA- and uPA-deficient  mice (E and F) with GN demonstrating light microscopic appearances (PAS stain, magnification ×350) and fibrin deposition  (immunofluorescence, magnification ×400). WT mice with  GN at day 10 showed proliferative GN (A) and segmental fibrin  deposition within the glomerular  tuft (B). Plg-deficient mice at day  8 developed hypocellular glomeruli with extensive deposition  of PAS+ material in the glomerular tuft and cellular crescent formation (C, arrowed) and extensive  fibrin deposition within the glomerular tuft and in Bowman's  space (D, arrowed). Mice with  combined tPA, uPA deficiency at  day 10 showed similar histological features to Plg-deficient mice  (E) and similar extensive glomerular fibrin deposition (F).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196158&req=5

Figure 1: Photomicrographs of representative glomeruli from WT mice (A and B, Plg-deficient mice (C and D) and combined tPA- and uPA-deficient mice (E and F) with GN demonstrating light microscopic appearances (PAS stain, magnification ×350) and fibrin deposition (immunofluorescence, magnification ×400). WT mice with GN at day 10 showed proliferative GN (A) and segmental fibrin deposition within the glomerular tuft (B). Plg-deficient mice at day 8 developed hypocellular glomeruli with extensive deposition of PAS+ material in the glomerular tuft and cellular crescent formation (C, arrowed) and extensive fibrin deposition within the glomerular tuft and in Bowman's space (D, arrowed). Mice with combined tPA, uPA deficiency at day 10 showed similar histological features to Plg-deficient mice (E) and similar extensive glomerular fibrin deposition (F).
Mentions: All WT mice developed proliferative GN (Fig. 1 A) with occasional glomeruli exhibiting crescent formation. Areas of basement membrane thickening were demonstrated by silver methenamine staining (not shown) and segmental fibrin deposition was observed within the glomerular tuft by direct immunofluorescence (Fig. 1 B). Glomeruli of both Plg−/− and tPA−/−:uPA−/− mice were more severely affected, with tuft necrosis and relatively hypocellular glomeruli (Fig. 1, C and E). Despite this relative hypocellularity, there were more macrophages within glomeruli and significantly increased numbers of glomeruli exhibiting crescent formation compared to their respective WT controls (Table 1). Crescents in the Plg−/− and tPA−/−: uPA−/− animals were larger than those found in WT mice and contained both cellular elements (Fig. 1, C and E, arrowed), and fibrin (Fig. 1, D and F, arrowed). Deposition of PAS+ material within glomeruli was significantly increased (Table 1) indicating more extra cellular matrix deposition in nephritic Plg−/− and tPA−/−:uPA−/− mice, compared to WT animals.

Bottom Line: The plasminogen/plasmin system has the potential to affect the outcome of inflammatory diseases by regulating accumulation of fibrin and other matrix proteins.Deficiency of tPA, the predominant plasminogen activator expressed in glomeruli, also exacerbated disease. uPA deficiency reduced glomerular macrophage infiltration and did not significantly exacerbate disease. uPA receptor deficiency did not effect the expression of GN.These studies demonstrate that plasminogen plays an important role in protecting the glomerulus from acute inflammatory injury and that tPA is the major protective plasminogen activator.

View Article: PubMed Central - PubMed

Affiliation: Center for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Victoria, Australia.

ABSTRACT
The plasminogen/plasmin system has the potential to affect the outcome of inflammatory diseases by regulating accumulation of fibrin and other matrix proteins. In human and experimental crescentic glomerulonephritis (GN), fibrin is an important mediator of glomerular injury and renal impairment. Glomerular deposition of matrix proteins is a feature of progressive disease. To study the role of plasminogen and plasminogen activators in the development of inflammatory glomerular injury, GN was induced in mice in which the genes for these proteins had been disrupted by homologous recombination. Deficiency of plasminogen or combined deficiency of tissue type plasminogen activator (tPA) and urokinase type plasminogen activator (uPA) was associated with severe functional and histological exacerbation of glomerular injury. Deficiency of tPA, the predominant plasminogen activator expressed in glomeruli, also exacerbated disease. uPA deficiency reduced glomerular macrophage infiltration and did not significantly exacerbate disease. uPA receptor deficiency did not effect the expression of GN. These studies demonstrate that plasminogen plays an important role in protecting the glomerulus from acute inflammatory injury and that tPA is the major protective plasminogen activator.

Show MeSH
Related in: MedlinePlus