Lack of integrin alpha1beta1 leads to severe glomerulosclerosis after glomerular injury.
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.
Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University, Medical Center North, B3109, 1161 21st Ave., Nashville, TN 37212, USA.
Xiwu
X
Chen
Gilbert
G
Moeckel
Jason D
JD
Morrow
Dominic
D
Cosgrove
Raymond C
RC
Harris
Agnes B
AB
Fogo
Roy
R
Zent
Ambra
A
Pozzi
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000975:Antioxidants / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D024141:Collagen Type IV / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D005920:Glomerular Mesangium / Q000293:injuries*; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006720:Homozygote; D039222:Integrin alpha1beta1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017382:Reactive Oxygen Species / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D024141:Collagen Type IV; D039222:Integrin alpha1beta1; D017382:Reactive Oxygen Species; D004317:Doxorubicin