Journal
MOLECULAR GENETICS AND METABOLISM
Volume 104, Issue 3, Pages 373-382Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2011.07.025
Keywords
Collagen; Extracellular matrix; Glomerular sclerosis; Fibrosis; Matrix metalloproteinase
Funding
- Leda J. Sears Trust Foundation
- NIH/NIDDK [DK069522]
- NIH/Clinical Biodetectives Training Grant [R90-DK071510-03]
- NICHD
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Col1a2-deficient (oim) mice synthesize homotrimeric type I collagen due to nonfunctional pro alpha 2(1) collagen chains. Our previous studies revealed a postnatal, progressive type I collagen glomerulopathy in this mouse model, but the mechanism of the sclerotic collagen accumulation within the renal mesangium remains unclear. The recent demonstration of the resistance of homotrimeric type I collagen to cleavage by matrix metalloproteinases (MMPs), led us to investigate the role of MMP-resistance in the glomerulosclerosis of Col1a2-deficient mice. We measured the pre- and post-translational expression of type I collagen and MMPs in glomeruli from heterozygous and homozygous animals. Both the heterotrimeric and homotrimeric isotypes of type I collagen were equally present in whole kidneys of heterozygous mice by immunohistochemistry and biochemical analysis, but the sclerotic glomerular collagen was at least 95-98% homotrimeric, suggesting homotrimeric type I collagen is the pathogenic isotype of type I collagen in glomerular disease. Although steady-state MMP and Col1a1 mRNA levels increased with the disease progression, we found these changes to be a secondary response to the deficient clearance of MMP-resistant homotrimers. Increased renal MMP expression was not sufficient to prevent homotrimeric type I collagen accumulation. (C) 2011 Elsevier Inc. All rights reserved.
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