Matrix metalloproteinase‐12 deficiency attenuates experimental crescentic anti‐glomerular basement membrane glomerulonephritis

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Glomerular macrophage infiltration is a prominent feature in rapidly progressive human and experimental glomerulonephritis and is associated with glomerular injury, crescent formation, Bowman's capsule rupture and loss of kidney function.1 Animal studies have shown that depletion of macrophages significantly reduces the development of crescents and renal injury in models of antibody‐mediated glomerulonephritis.4 Therefore, understanding the mechanisms responsible for macrophage migration, accumulation and activation in diseased glomeruli may help identify novel strategies for suppressing the development of glomerulonephritis.
Upon activation, macrophages release proteases that degrade extracellular matrix which can result in either tissue destruction or repair. In fibrotic diseases in the kidney, heart and lungs, levels of macrophage‐secreted elastase (also known as matrix metalloproteinase‐12; MMP‐12) are elevated and correlate with tissue injury and fibrosis.5 MMP‐12 appears to be important for macrophage migration through tissues, because macrophages deficient in MMP‐12 have a reduced capacity to degrade matrix and penetrate basement membrane; however, the numbers of resident tissue macrophages in normal mice is unaffected by MMP‐12 deficiency.8 Studies in gene deficient mice have shown that MMP‐12 is required for macrophage infiltration and injury in lungs during smoke‐induced emphysema,9 and macrophage accumulation and fibrosis in the heart and skin following angiotensin II‐infusion.6 These studies also suggest that MMP‐12 plays a role in the phenotype and function of macrophages. Therefore, MMP‐12 has the capacity to regulate macrophage‐mediated injury in some diseases.
In the kidney, MMP‐12 mRNA levels and protein levels are markedly increased in mice and rats with anti‐glomerular basement membrane (GBM) glomerulonephritis. Furthermore, macrophages isolated from mouse kidneys with anti‐GBM glomerulonephritis have a marked increase in MMP12 mRNA levels.10 In addition, a study using a c‐fms inhibitor has demonstrated that selective blockade of macrophage accumulation in anti‐GBM glomerulonephritis abolishes MMP‐12 expression,4 demonstrating that macrophages are the main or sole source of kidney MMP‐12 in this disease.
A polyclonal antibody neutralizing rat MMP‐12 has been shown to inhibit the development of rat anti‐GBM glomerulonephritis,5 thereby identifying MMP‐12 as a therapeutic target in this disease. However, it is unclear whether this strategy completely neutralizes MMP‐12 in the kidney, and therefore, the full potential of MMP‐12 blockade in this disease may be underestimated. Also, it is likely that polyclonal antibodies targeting MMP‐12 will, at least partially, inhibit other MMPs, because these are highly conserved enzymes with similar catalytic domains.11 Other MMPs, such as MMP‐2 and MMP‐9 are also elevated in glomeruli during rat anti‐GBM glomerulonephritis,12 and MMP‐9 deficiency is protective in mice with anti‐GBM glomerulonephritis.13 Therefore, in order to better define the role of MMP‐12 in glomerulonephritis, we examined development of anti‐GBM disease in mice with a genetic deficiency of MMP‐12.
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