Integrin alpha1beta1 Regulates Matrix Metalloproteinases via P38 Mitogen-Activated Protein Kinase in Mesangial Cells: Implications for Alport Syndrome

Am J Pathol. 2008 Mar;172(3):761-73. doi: 10.2353/ajpath.2008.070473. Epub 2008 Feb 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoantigens / genetics
  • Biphenyl Compounds
  • Cells, Cultured
  • Collagen Type IV / genetics
  • Disease Models, Animal
  • Gene Expression Regulation, Enzymologic* / drug effects
  • Integrin alpha1beta1 / genetics
  • Integrin alpha1beta1 / physiology*
  • Matrix Metalloproteinases / genetics*
  • Matrix Metalloproteinases / metabolism
  • Mesangial Cells / enzymology*
  • Mesangial Cells / metabolism
  • Mice
  • Mice, Knockout
  • Nephritis, Hereditary / enzymology
  • Nephritis, Hereditary / genetics*
  • Nephritis, Hereditary / pathology
  • Organic Chemicals / pharmacology
  • Phenylbutyrates
  • Tissue Inhibitor of Metalloproteinases / genetics
  • Tissue Inhibitor of Metalloproteinases / metabolism
  • p38 Mitogen-Activated Protein Kinases / physiology*

Substances

  • Autoantigens
  • Biphenyl Compounds
  • Collagen Type IV
  • Integrin alpha1beta1
  • Organic Chemicals
  • Phenylbutyrates
  • Tissue Inhibitor of Metalloproteinases
  • type IV collagen alpha3 chain
  • Bay 12-9566
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinases