Lack of integrin alpha1beta1 leads to severe glomerulosclerosis after glomerular injury

Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University, Medical Center North, B3109, 1161 21st Ave., Nashville, TN 37212, USA.
American Journal Of Pathology (Impact Factor: 4.59). 09/2004; 165(2):617-30.
Source: PubMed


Severity of fibrosis after injury is determined by the nature of the injury and host genetic susceptibility. Metabolism of collagen, the major component of fibrotic lesions, is, in part, regulated by integrins. Using a model of glomerular injury by adriamycin, which induces reactive oxygen species (ROS) production, we demonstrated that integrin alpha1-null mice develop more severe glomerulosclerosis than wild-type mice. Moreover, primary alpha1-null mesangial cells produce more ROS both at baseline and after adriamycin treatment. Increased ROS synthesis leads to decreased cell proliferation and increased glomerular collagen IV accumulation that is reversed by antioxidants both in vivo and in vitro. Thus, we have identified integrin alpha1beta1 as a modulator of glomerulosclerosis. In addition, we showed a novel pathway where integrin alpha1beta1 modulates ROS production, which in turn controls collagen turnover and ultimately fibrosis. Because integrin alpha1beta1 is expressed in many cell types this may represent a generalized mechanism of controlling matrix accumulation, which has implications for numerous diseases characterized by fibrosis.

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    • "Integrin α1β1, believed to function primarily as receptor for type IV collagen [47], has been shown previously to be upregulated in proliferating mesangial cells in glomerulonephritis [48], [49]. This integrin also negatively mediates collagen IV synthesis and integrin α1 null mice suffer more severe glomerular fibrosis after renal injury [50], [51]. On the other hand, Alport mice with genetic deletion of integrin α1 experience less mesangial matrix expansion and reduced podocyte foot process effacement [11]. "
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