Role for macrophage metalloelastase in glomerular basement membrane damage associated with alport syndrome.
Alport syndrome is a glomerular basement membrane (GBM) disease caused by mutations in type IV collagen genes. A unique irregular thickening and thinning of the GBM characterizes the progressive glomerular pathology. The metabolic imbalances responsible for these GBM irregularities are not known. Here we show that macrophage metalloelastase (MMP-12) expression is >40-fold induced in glomeruli from Alport mice and is markedly induced in glomeruli of both humans and dogs with Alport syndrome. Treatment of Alport mice with MMI270 (CGS27023A), a broad spectrum MMP inhibitor that blocks MMP-12 activity, results in largely restored GBM ultrastructure and function. Treatment with BAY-129566, a broad spectrum MMP inhibitor that does not inhibit MMP-12, had no effect. We show that inhibition of CC chemokine receptor 2 (CCR2) receptor signaling with propagermanium blocks induction of MMP-12 mRNA and prevents GBM damage. CCR2 receptor is expressed in glomerular podocytes of Alport mice, suggesting MCP-1 activation of CCR2 on podocytes may underlie induction of MMP-12. These data indicate that the irregular GBM that characterizes Alport syndrome may be mediated, in part, by focal degradation of the GBM due to MMP dysregulation, in particular, MMP-12. Thus, MMP-12/CCR2 inhibitors may provide a novel and effective therapeutic stra-tegy for Alport glomerular disease.
Rao
Velidi H
VH
Boys Town National Research Hospital, 555 No. 30th St., Omaha, NE 68131, USA.
Meehan
Daniel T
DT
Delimont
Duane
D
Nakajima
Motowo
M
Wada
Takashi
T
Gratton
Michael Ann
MA
Cosgrove
Dominic
D
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050533:Glomerular Basement Membrane / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009394:Nephritis, Hereditary / Q000201:enzymology* / Q000473:pathology*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D004791:Enzyme Inhibitors; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12