TY - JOUR
T1 - Integrin α1β1 regulates matrix metalloproteinases via p38 mitogen-activated protein kinase in mesangial cells
T2 - Implications for alport syndrome
AU - Cosgrove, Dominic
AU - Meehan, Daniel T.
AU - Delimont, Duane
AU - Pozzi, Ambra
AU - Chen, Xiwu
AU - Rodgers, Kathyrn D.
AU - Tempero, Richard M.
AU - Zallocchi, Marisa
AU - Rao, Velidi H.
N1 - Funding Information:
Supported by the National Institutes of Health (grants R01 DK55000 and R01 DC04844 to D.C. and RO1 CA94849-01 to A.P. ).
PY - 2008/3
Y1 - 2008/3
N2 - Previous work has shown that integrin α1-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 α1-null mice and integrin α1-null Alport mice relative to wild-type mice; however, only MMP-9 was elevated in glomeruli of Alport mice that express integrin α1. Similarly, cultured mesangial cells from α1-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 α1-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 α1-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 α1 integrin-null Alport mice, suggesting that elevated gelatinase activity exacerbates glomerular disease progression in these mice.
AB - Previous work has shown that integrin α1-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 α1-null mice and integrin α1-null Alport mice relative to wild-type mice; however, only MMP-9 was elevated in glomeruli of Alport mice that express integrin α1. Similarly, cultured mesangial cells from α1-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 α1-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 α1-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 α1 integrin-null Alport mice, suggesting that elevated gelatinase activity exacerbates glomerular disease progression in these mice.
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U2 - 10.2353/ajpath.2008.070473
DO - 10.2353/ajpath.2008.070473
M3 - Article
C2 - 18258846
AN - SCOPUS:40449098083
SN - 0002-9440
VL - 172
SP - 761
EP - 773
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -