Integrin alpha1beta1 regulates matrix metalloproteinases via P38 mitogen-activated protein kinase in mesangial cells: implications for Alport syndrome.

Cosgrove D, Meehan DT, Delimont D, Pozzi A, Chen X, Rodgers KD, Tempero RM, Zallocchi M, Rao VH
Am J Pathol. 2008 172 (3): 761-73

PMID: 18258846 · PMCID: PMC2258247 · DOI:10.2353/ajpath.2008.070473

Previous work has shown that integrin alpha1-null Alport mice exhibit attenuated glomerular disease with decreased matrix accumulation and live much longer than strain-matched Alport mice. However, the mechanism underlying this observation is unknown. Here we show that glomerular gelatinase expression, specifically matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-14, was significantly elevated in both integrin alpha1-null mice and integrin alpha1-null Alport mice relative to wild-type mice; however, only MMP-9 was elevated in glomeruli of Alport mice that express integrin alpha1. Similarly, cultured mesangial cells from alpha1-null mice showed elevated expression levels of all three MMPs, whereas mesangial cells from Alport mice show elevated expression levels of only MMP-9. In both glomeruli and cultured mesangial cells isolated from integrin alpha1-null mice, activation of the p38 and ERK branches of the mitogen-activated protein kinase pathway was also observed. The use of small molecule inhibitors demonstrated that the activation of the p38, but not ERK, pathway was linked to elevated MMP-2, -9, and -14 expression levels in mesangial cells from integrin alpha1-null mice. In contrast, elevated MMP-9 levels in mesangial cells from Alport mice were linked to ERK pathway activation. Blockade of gelatinase activity using a small molecule inhibitor (BAY-12-9566) ameliorated progression of proteinuria and restored the architecture of the glomerular basement membrane in alpha1 integrin-null Alport mice, suggesting that elevated gelatinase activity exacerbates glomerular disease progression in these mice.

MeSH Terms (17)

Animals Autoantigens Biphenyl Compounds Cells, Cultured Collagen Type IV Disease Models, Animal Gene Expression Regulation, Enzymologic Integrin alpha1beta1 Matrix Metalloproteinases Mesangial Cells Mice Mice, Knockout Nephritis, Hereditary Organic Chemicals p38 Mitogen-Activated Protein Kinases Phenylbutyrates Tissue Inhibitor of Metalloproteinases

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