Transforming growth factor-β-dependent and-independent pathways of induction of tubulointerstitial fibrosis in β6−/− mice

LJ Ma, H Yang, A Gaspert, G Carlesso, MM Barty… - The American journal of …, 2003 - Elsevier
LJ Ma, H Yang, A Gaspert, G Carlesso, MM Barty, JM Davidson, D Sheppard, AB Fogo
The American journal of pathology, 2003Elsevier
Transforming growth factor-β1 (TGF-β1) and the renin-angiotensin-aldosterone system are
key mediators in kidney fibrosis. Integrin αvβ6, a heterodimeric matrix receptor expressed in
epithelia, binds and activates latent TGF-β1. We used β6 integrin-null mice (β6−/−) to
determine the role of local TGF-β1 activation in renal fibrosis in the unilateral ureteral
obstruction (UUO) model. Obstructed kidneys from β6−/− mice showed less injury than
obstructed kidneys from wild-type (WT) mice, associated with lower collagen I, collagen III …
Transforming growth factor-β1 (TGF-β1) and the renin-angiotensin-aldosterone system are key mediators in kidney fibrosis. Integrin αvβ6, a heterodimeric matrix receptor expressed in epithelia, binds and activates latent TGF-β1. We used β6 integrin-null mice (β6−/−) to determine the role of local TGF-β1 activation in renal fibrosis in the unilateral ureteral obstruction (UUO) model. Obstructed kidneys from β6−/− 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-β1 mRNA levels and lower collagen content. Infusion with either angiotensin II (Ang II) or aldosterone (Aldo) or combination in β6−/− UUO mice significantly increased collagen contents to levels comparable to those in identically treated WT. Active TGF-β protein expression in β6−/− mice was less in UUO kidneys with or without Ang II infusion compared to matched WT mice. Activated Smad 2 levels in β6−/− obstructed kidneys were lower than in WT UUO mice, and did not increase when fibrosis was induced in β6−/− UUO mice by Ang II infusion. Anti-TGF-β antibody only partially decreased this Ang II-stimulated fibrosis in β6−/− UUO kidneys. In situ hybridization and immunostaining showed low expression of PAI-1 mRNA and protein in tubular epithelium in β6−/− UUO kidneys, with increased PAI-1 expression in response to Ang II, Aldo, or both. Our results indicate that interruption of αvβ6-mediated activation of TGF-β1 can protect against tubulointerstitial fibrosis. Further, the robust induction of tubulointerstitial fibrosis without increase in activated Smad 2 levels in obstructed β6−/− mice by Ang II suggests the existence of a TGF-β1-independent pathway of induction of fibrosis through angiotensin.
Elsevier