Published online before print February 7, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070473

Accepted for publication November 26, 2007.

Article

Integrin 11 Regulates Matrix Metalloproteinases via P38 Mitogen-Activated Protein Kinase in Mesangial Cells. Implications for Alport Syndrome

Dominic Cosgrove^*@, Daniel T. Meehan^*, Duane Delimont^*, Ambra Pozzi, Xiwu Chen, Kathyrn D. Rodgers, Richard M. Tempero^*, Marisa Zallocchi^*, and Velidi H. Rao^*

From Boys Town National Research Hospital,* Omaha, Nebraska; the Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University, Nashville, Tennessee; and the University of Pennsylvania School of Veterinary Sciences, Philadelphia, Pennsylvania

^@ To whom correspondence should be addressed. E-mail: cosgrove{at}boystown.org.

	Abstract

Previous work has shown that integrin 1-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 1-null mice and integrin 1-null Alport mice relative to wild-type mice; however, only MMP-9 was elevated in glomeruli of Alport mice that express integrin 1. Similarly, cultured mesangial cells from 1-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 1-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 1-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 1 integrin-null Alport mice, suggesting that elevated gelatinase activity exacerbates glomerular disease progression in these mice.

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