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

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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)761-773
Number of pages13
JournalAmerican Journal of Pathology
Volume172
Issue number3
DOIs
StatePublished - Mar 2008

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Matrix Metalloproteinase 11
Hereditary Nephritis
Mesangial Cells
p38 Mitogen-Activated Protein Kinases
Integrins
Matrix Metalloproteinases
Gelatinases
MAP Kinase Signaling System
Matrix Metalloproteinase 2
Cultured Cells
Glomerular Basement Membrane
Matrix Metalloproteinase 9

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Integrin α1β1 regulates matrix metalloproteinases via p38 mitogen-activated protein kinase in mesangial cells : Implications for alport syndrome. / Cosgrove, Dominic E; Meehan, Daniel T.; Delimont, Duane; Pozzi, Ambra; Chen, Xiwu; Rodgers, Kathyrn D.; Tempero, Richard M; Zallocchi, Marisa L; Rao, Velidi H.

In: American Journal of Pathology, Vol. 172, No. 3, 03.2008, p. 761-773.

Research output: Contribution to journalArticle

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