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From the Department of Pathology,* Vanderbilt University Medical Center, Nashville, Tennessee; Research Service, Veteran’s Administration Medical Center, Nashville, Tennessee; and the Lung Biology Center, University of California, San Francisco, California
Transforming growth factor-ß1 (TGF-ß1) and the renin-angiotensin-aldosterone system are key mediators in kidney fibrosis. Integrin 
vß6, a heterodimeric matrix receptor expressed in epithelia, binds and activates latent TGF-ß1. We used ß6 integrin-null mice (ß6-/-) to determine the role of local TGF-ß1 activation in renal fibrosis in the unilateral ureteral obstruction (UUO) model. Obstructed kidneys from ß6-/- mice showed less injury than obstructed kidneys from wild-type (WT) mice, associated with lower collagen I, collagen III, plasminogen activator inhibitor (PAI-1), and TGF-ß1 mRNA levels and lower collagen content. Infusion with either angiotensin II (Ang II) or aldosterone (Aldo) or combination in ß6-/- UUO mice significantly increased collagen contents to levels comparable to those in identically treated WT. Active TGF-ß protein expression in ß6-/- mice was less in UUO kidneys with or without Ang II infusion compared to matched WT mice. Activated Smad 2 levels in ß6-/- obstructed kidneys were lower than in WT UUO mice, and did not increase when fibrosis was induced in ß6-/- UUO mice by Ang II infusion. Anti-TGF-ß antibody only partially decreased this Ang II-stimulated fibrosis in ß6-/- UUO kidneys. In situ hybridization and immunostaining showed low expression of PAI-1 mRNA and protein in tubular epithelium in ß6-/- UUO kidneys, with increased PAI-1 expression in response to Ang II, Aldo, or both. Our results indicate that interruption of vß6-mediated activation of TGF-ß1 can protect against tubulointerstitial fibrosis. Further, the robust induction of tubulointerstitial fibrosis without increase in activated Smad 2 levels in obstructed ß6-/- mice by Ang II suggests the existence of a TGF-ß1-independent pathway of induction of fibrosis through angiotensin.
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