Integrin alpha1beta1 regulates matrix metalloproteinases via P38 mitogen-activated protein kinase in mesangial cells: implications for Alport syndrome.
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.
Cosgrove
Dominic
D
Boys Town National Research Hospital, 555 No. 30th St., Omaha, NE 68131, USA. cosgrove@boystown.org
Meehan
Daniel T
DT
Delimont
Duane
D
Pozzi
Ambra
A
Chen
Xiwu
X
Rodgers
Kathyrn D
KD
Tempero
Richard M
RM
Zallocchi
Marisa
M
Rao
Velidi H
VH
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*
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