title: Integrin alpha1beta1 regulates matrix metalloproteinases via P38 mitogen-activated protein kinase in mesangial cells: implications for Alport syndrome.
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.
authors.affiliation: Boys Town National Research Hospital, 555 No. 30th St., Omaha, NE 68131, USA. cosgrove@boystown.org
authors.forename: Dominic
authors.initials: D
authors.lastname: Cosgrove
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meehan
authors.forename: Duane
authors.initials: D
authors.lastname: Delimont
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.forename: Xiwu
authors.initials: X
authors.lastname: Chen
authors.forename: Kathyrn D
authors.initials: KD
authors.lastname: Rodgers
authors.forename: Richard M
authors.initials: RM
authors.lastname: Tempero
authors.forename: Marisa
authors.initials: M
authors.lastname: Zallocchi
authors.forename: Velidi H
authors.initials: VH
authors.lastname: Rao
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000235:genetics; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D039222:Integrin alpha1beta1 / Q000235:genetics / Q000502:physiology*; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D050527:Mesangial Cells / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009930:Organic Chemicals / Q000494:pharmacology; D010654:Phenylbutyrates; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D001324:Autoantigens; D001713:Biphenyl Compounds; D024141:Collagen Type IV; D039222:Integrin alpha1beta1; D009930:Organic Chemicals; D010654:Phenylbutyrates; D019714:Tissue Inhibitor of Metalloproteinases; C057112:type IV collagen alpha3 chain; C113281:Bay 12-9566; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases