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(American Journal of Pathology. 2004;165:617-630.)
© 2004 American Society for Investigative Pathology

Lack of Integrin 1ß1 Leads to Severe Glomerulosclerosis after Glomerular Injury

Xiwu Chen^*, Gilbert Moeckel, Jason D. Morrow, Dominic Cosgrove, Raymond C. Harris^*¶, Agnes B. Fogo, Roy Zent^*¶|| and Ambra Pozzi^*¶||

From the Department of Medicine,^* Division of Nephrology, and the Departments of Pathology, Pharmacology, and Cancer Biology,^|| Vanderbilt University Medical Center, Nashville, Tennessee; the Veterans Affairs Hospital,^¶ Nashville, Tennessee; and the Department of Cancer Genetics, Boys Town National Research Hospital, Omaha, Nebraska

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 1-null mice develop more severe glomerulosclerosis than wild-type mice. Moreover, primary 1-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 1ß1 as a modulator of glomerulosclerosis. In addition, we showed a novel pathway where integrin 1ß1 modulates ROS production, which in turn controls collagen turnover and ultimately fibrosis. Because integrin 1ß1 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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