In chronic renal disease the progressive accumulation of collagen in the glomerular mesangial matrix is a major pathological consequence, culminating in glomerulosclerosis, and renal failure. The production of excess extracellular matrix (ECM) is hypothesized to result from over compensation of the glomerular wound healing response. Though much is known concerning the initiating events leading to accumulation of the ECM, very little is known mechanistically about the role of the ECM in the pathogenesis of the glomerular mesangial cell response. Recently, we identified a novel collagen glomerulopathy in a proa2(l)collagen deficient mouse (oim), which promises to provide new insight into the regulatory role of type I collagen in the pathogenesis of glomerular disease. Oim/oim mice (homozygous null for the COL1A2 gene) are unique in that they exclusively synthesize homotrimeric type I collagen, a1(l)3, and are unable to synthesize normal heterotrimeric type I collagen, a1(l)2a2(l). Lacking a2(l) collagen chains results in deposition of homotrimeric type I collagen in the glomerular mesangium. In contrast to intact healthy kidney where no type I collagen is normally present in the glomeruli, collagen deposition and glomerular expansion are common features contributing to progressive renal disease and failure, suggesting that homotrimeric type I collagen may play an important role in the pathogenesis of glomerulosclerosis. Our long term goal is to understand the molecular mechanisms involved in the ECM deposition and pathogenesis of glomerulosclerosis in order to identify targets for therapeutic interventions. Towards this end we propose to 1) characterize the natural progression of the collagen type I glomerulopathy in oim/oim mice and to correlate pathological findings with disease progression, 2) to determine mechanistically whether type I collagen deposition in the oim/oim glomeruli is a consequence of increased collagen expression or aberrant matrix degradation, and 3) to determine if matrix metalloproteinases differentially cleave homotrimeric and heterotrimeric type I collagen. ? ?
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| Makareeva, Elena; Han, Sejin; Vera, Juan Carlos et al. (2010) Carcinomas contain a matrix metalloproteinase-resistant isoform of type I collagen exerting selective support to invasion. Cancer Res 70:4366-74 |
| Brodeur, A C; Wirth, D A; Franklin, C L et al. (2007) Type I collagen glomerulopathy: postnatal collagen deposition follows glomerular maturation. Kidney Int 71:985-93 |
