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Matrix metalloproteinase 9 protects mice from anti-glomerular basement membrane nephritis through its fibrinolytic activity.

Lelongt B, Bengatta S, Delauche M, Lund LR, Werb Z, Ronco PM - J. Exp. Med. (2001)

Bottom Line: Matrix metalloproteinase (MMP)9/gelatinase B is increased in various nephropathies.However, we found that fibrin is a critical substrate for MMP9, and in its absence fibrin accumulated in the glomeruli.These data indicate that MMP9 is required for a novel protective effect on the development of fibrin-induced glomerular lesions.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 489, Hôpital Tenon and Université Pierre et Marie Curie (Paris 6), 75020 Paris, France. brigitte.lelongt@tnn.ap-hop-paris.fr

ABSTRACT
Matrix metalloproteinase (MMP)9/gelatinase B is increased in various nephropathies. To investigate its role, we used a genetic approach. Adult MMP9-deficient (MMP9(-/)-) mice showed normal renal histology and function at 3 mo. We investigated the susceptibility of 3-mo-old mice to the accelerated model of anti-glomerular basement membrane nephritis, in which fibrin is an important mediator of glomerular injury and renal impairment. Unexpectedly, nephritis was more severe in MMP9(-/)- than in control mice, as attested by levels of serum creatinine and albuminuria, and the extent of crescents and fibrin deposits. Circulating or deposited immunoglobulin G, interleukin (IL)-1beta, or IL-10 were the same in MMP9(-/-) and MMP9(+/+) mice. However, we found that fibrin is a critical substrate for MMP9, and in its absence fibrin accumulated in the glomeruli. These data indicate that MMP9 is required for a novel protective effect on the development of fibrin-induced glomerular lesions.

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Effect of MMP9 deficiency on renal function in anti-GBM glomerulonephritis. (A) Serum creatinine (Creat.), protein (Prot.), and albumin (Alb.) levels in MMP9+/+ (hatched bars) and MMP9−/− (white bars) mice. n = 25. (B) Urinary parameters. Urine was collected for 24 h from MMP9+/+ (hatched bars) and MMP9−/− (white bars) mice housed in metabolic cages, and results were expressed as the ratio of albumin to creatinine (Alb./Creat.) or as daily proteinuria (Prot./day). Sera and urine were collected 15 d after injection of anti-GBM antibody. Values in noninjected MMP9+/+ mice were: albumin/creatinine = 10.23 ± 0.97; proteinuria/day = 4.01 ± 2.16. Values in noninjected MMP9−/− mice were almost identical to control MMP9+/+ mice: albumin/creatinine = 9.76 ± 1.02; proteinuria/day = 4.21 ± 1.36. Values are mean ± SEM; *P < 0.02, **P < 0.01 versus MMP9+/+ control mice. n = 15.
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Figure 1: Effect of MMP9 deficiency on renal function in anti-GBM glomerulonephritis. (A) Serum creatinine (Creat.), protein (Prot.), and albumin (Alb.) levels in MMP9+/+ (hatched bars) and MMP9−/− (white bars) mice. n = 25. (B) Urinary parameters. Urine was collected for 24 h from MMP9+/+ (hatched bars) and MMP9−/− (white bars) mice housed in metabolic cages, and results were expressed as the ratio of albumin to creatinine (Alb./Creat.) or as daily proteinuria (Prot./day). Sera and urine were collected 15 d after injection of anti-GBM antibody. Values in noninjected MMP9+/+ mice were: albumin/creatinine = 10.23 ± 0.97; proteinuria/day = 4.01 ± 2.16. Values in noninjected MMP9−/− mice were almost identical to control MMP9+/+ mice: albumin/creatinine = 9.76 ± 1.02; proteinuria/day = 4.21 ± 1.36. Values are mean ± SEM; *P < 0.02, **P < 0.01 versus MMP9+/+ control mice. n = 15.

Mentions: We observed no significant difference in renal function and histological features between MMP9−/− and MMP9+/+ mice at the heterologous phase that occurs 24 h after the injection of sheep anti-GBM antibody (data not shown). At the autologous phase, 15 d after the injection of the anti-GBM antibody, both control and MMP9−/− mice developed a crescentic proliferative glomerulonephritis. Surprisingly, the renal failure was more severe in MMP9−/− mice (Fig. 1 A). These mice also showed a markedly increased urinary protein loss, expressed as albumin over creatinine ratio or daily proteinuria, compared with MMP9+/+ mates (Fig. 1 B). However, serum total proteins and serum albumin did not differ between the two groups.


Matrix metalloproteinase 9 protects mice from anti-glomerular basement membrane nephritis through its fibrinolytic activity.

Lelongt B, Bengatta S, Delauche M, Lund LR, Werb Z, Ronco PM - J. Exp. Med. (2001)

Effect of MMP9 deficiency on renal function in anti-GBM glomerulonephritis. (A) Serum creatinine (Creat.), protein (Prot.), and albumin (Alb.) levels in MMP9+/+ (hatched bars) and MMP9−/− (white bars) mice. n = 25. (B) Urinary parameters. Urine was collected for 24 h from MMP9+/+ (hatched bars) and MMP9−/− (white bars) mice housed in metabolic cages, and results were expressed as the ratio of albumin to creatinine (Alb./Creat.) or as daily proteinuria (Prot./day). Sera and urine were collected 15 d after injection of anti-GBM antibody. Values in noninjected MMP9+/+ mice were: albumin/creatinine = 10.23 ± 0.97; proteinuria/day = 4.01 ± 2.16. Values in noninjected MMP9−/− mice were almost identical to control MMP9+/+ mice: albumin/creatinine = 9.76 ± 1.02; proteinuria/day = 4.21 ± 1.36. Values are mean ± SEM; *P < 0.02, **P < 0.01 versus MMP9+/+ control mice. n = 15.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193369&req=5

Figure 1: Effect of MMP9 deficiency on renal function in anti-GBM glomerulonephritis. (A) Serum creatinine (Creat.), protein (Prot.), and albumin (Alb.) levels in MMP9+/+ (hatched bars) and MMP9−/− (white bars) mice. n = 25. (B) Urinary parameters. Urine was collected for 24 h from MMP9+/+ (hatched bars) and MMP9−/− (white bars) mice housed in metabolic cages, and results were expressed as the ratio of albumin to creatinine (Alb./Creat.) or as daily proteinuria (Prot./day). Sera and urine were collected 15 d after injection of anti-GBM antibody. Values in noninjected MMP9+/+ mice were: albumin/creatinine = 10.23 ± 0.97; proteinuria/day = 4.01 ± 2.16. Values in noninjected MMP9−/− mice were almost identical to control MMP9+/+ mice: albumin/creatinine = 9.76 ± 1.02; proteinuria/day = 4.21 ± 1.36. Values are mean ± SEM; *P < 0.02, **P < 0.01 versus MMP9+/+ control mice. n = 15.
Mentions: We observed no significant difference in renal function and histological features between MMP9−/− and MMP9+/+ mice at the heterologous phase that occurs 24 h after the injection of sheep anti-GBM antibody (data not shown). At the autologous phase, 15 d after the injection of the anti-GBM antibody, both control and MMP9−/− mice developed a crescentic proliferative glomerulonephritis. Surprisingly, the renal failure was more severe in MMP9−/− mice (Fig. 1 A). These mice also showed a markedly increased urinary protein loss, expressed as albumin over creatinine ratio or daily proteinuria, compared with MMP9+/+ mates (Fig. 1 B). However, serum total proteins and serum albumin did not differ between the two groups.

Bottom Line: Matrix metalloproteinase (MMP)9/gelatinase B is increased in various nephropathies.However, we found that fibrin is a critical substrate for MMP9, and in its absence fibrin accumulated in the glomeruli.These data indicate that MMP9 is required for a novel protective effect on the development of fibrin-induced glomerular lesions.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 489, Hôpital Tenon and Université Pierre et Marie Curie (Paris 6), 75020 Paris, France. brigitte.lelongt@tnn.ap-hop-paris.fr

ABSTRACT
Matrix metalloproteinase (MMP)9/gelatinase B is increased in various nephropathies. To investigate its role, we used a genetic approach. Adult MMP9-deficient (MMP9(-/)-) mice showed normal renal histology and function at 3 mo. We investigated the susceptibility of 3-mo-old mice to the accelerated model of anti-glomerular basement membrane nephritis, in which fibrin is an important mediator of glomerular injury and renal impairment. Unexpectedly, nephritis was more severe in MMP9(-/)- than in control mice, as attested by levels of serum creatinine and albuminuria, and the extent of crescents and fibrin deposits. Circulating or deposited immunoglobulin G, interleukin (IL)-1beta, or IL-10 were the same in MMP9(-/-) and MMP9(+/+) mice. However, we found that fibrin is a critical substrate for MMP9, and in its absence fibrin accumulated in the glomeruli. These data indicate that MMP9 is required for a novel protective effect on the development of fibrin-induced glomerular lesions.

Show MeSH
Related in: MedlinePlus