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.
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.
Authors: Yingjie Han; Frank Y Ma; Julie Di Paolo; David J Nikolic-Paterson Journal: Int J Immunopathol Pharmacol Date: 2018 Jan-Dec Impact factor: 3.219
Authors: Liv A Amos; Frank Y Ma; Greg H Tesch; John T Liles; David G Breckenridge; David J Nikolic-Paterson; Yingjie Han Journal: J Cell Mol Med Date: 2018-07-11 Impact factor: 5.310