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Matrix metalloproteinase-12 deficiency attenuates experimental crescentic anti-glomerular basement membrane
Abu P Abraham1,2, Frank Y Ma1,2, William R Mulley1,2
1Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia.
Aim:
Matrix metalloproteinase-12 (MMP-12; macrophage elastase) is an enzyme that can cleave various extracellular matrix proteins and is required for macrophage infiltration and pulmonary fibrosis in experimental emphysema. We have shown previously that MMP-12 is highly up-regulated in experimental anti-glomerular basement membrane (GBM) disease. The aim of this study was to determine whether MMP-12 is required for glomerular macrophage infiltration and crescent formation in anti-GBM glomerulonephritis.
Methods:
Accelerated anti-GBM disease was induced in groups of MMP-12 gene deficient mice (MMP-12-/-) and wild-type C57BL/6J controls, which were killed 12 days after injection of anti-GBM serum.
Results:
Wild-type and MMP-12-/- mice developed glomerular damage and glomerular tuft adhesions to Bowman's capsule. Both groups developed severe proteinuria. Wild-type mice also developed significant loss of renal function and crescents in 22% of glomeruli, which were associated with macrophage infiltration and Bowman's capsule rupture. In contrast, MMP-12-/- mice were partially protected from renal function decline, crescent formation and Bowman's capsule rupture. This was associated with reduced macrophage infiltration in both glomeruli and the interstitium, and with reduced expression of CCL2, TNF-α and iNOS mRNA in MMP-12-/- kidneys. In addition, KIM-1 mRNA levels were reduced in MMP-12-/- mice indicating less tubular damage.
Conclusion:
These data demonstrate that endogenous MMP-12 facilitates macrophage accumulation and activation in anti-GBM glomerulonephritis which is required for glomerular crescent formation, Bowman's capsule rupture, tubular damage and renal function decline.
Insights
Matrix metalloproteinase-12 (MMP-12) deficiency protects against anti-GBM glomerulonephritis by reducing macrophage infiltration and crescent formation. MMP-12 plays a key role in kidney damage progression in this disease model.
Area of Science:
- Nephrology
- Immunology
- Biochemistry
Background:
- Matrix metalloproteinase-12 (MMP-12), also known as macrophage elastase, degrades extracellular matrix proteins and is implicated in macrophage infiltration.
- MMP-12 is upregulated in experimental anti-glomerular basement membrane (GBM) disease.
- The role of MMP-12 in anti-GBM glomerulonephritis pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the requirement of MMP-12 in glomerular macrophage infiltration and crescent formation in a mouse model of anti-GBM glomerulonephritis.
Main Methods:
- Accelerated anti-GBM glomerulonephritis was induced in MMP-12 gene-deficient (MMP-12-/-) and wild-type mice.
- Mice were analyzed 12 days post-induction for renal function, glomerular damage, crescent formation, and macrophage infiltration.
Main Results:
- MMP-12-/- mice showed partial protection against renal function decline, crescent formation, and Bowman's capsule rupture compared to wild-type mice.
- Reduced macrophage infiltration in glomeruli and interstitium was observed in MMP-12-/- mice.
- Lower expression of CCL2, TNF-α, and iNOS mRNA, and reduced KIM-1 mRNA levels indicated less inflammation and tubular damage in MMP-12-/- kidneys.
Conclusions:
- Endogenous MMP-12 promotes macrophage accumulation and activation in anti-GBM glomerulonephritis.
- MMP-12 is essential for glomerular crescent formation, Bowman's capsule rupture, tubular damage, and subsequent renal function decline in this disease model.
