Integrin α1β1 regulates matrix metalloproteinases via p38 mitogen-activated protein kinase in mesangial cells -: Implications for Alport syndrome

Previous work has shown that integrin alpha 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 alpha 1-null mice and integrin alpha 1-null Alport mice relative to wild type mice; however, only MMP-9 was elevated in glomeruli of Alport mice that express integrin alpha 1. Similarly, cultured mesangial cells from alpha 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 alpha 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 alpha 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 129566) ameliorated progression of proteinuria and restored die architecture of the glomerular basement membrane in alpha 1 integrin-mill Alport mice, suggesting that elevated gelatinase activity exacerbates glomerular disease progression in these mice.