Transforming growth factor-beta-dependent and -independent pathways of induction of tubulointerstitial fibrosis in beta6(-/-) mice.

Ma LJ, Yang H, Gaspert A, Carlesso G, Barty MM, Davidson JM, Sheppard D, Fogo AB
Am J Pathol. 2003 163 (4): 1261-73

PMID: 14507636 · PMCID: PMC1868298 · DOI:10.1016/s0002-9440(10)63486-4

Transforming growth factor-beta1 (TGF-beta1) and the renin-angiotensin-aldosterone system are key mediators in kidney fibrosis. Integrin alphavbeta6, a heterodimeric matrix receptor expressed in epithelia, binds and activates latent TGF-beta1. We used beta6 integrin-null mice (beta6(-/-)) to determine the role of local TGF-beta1 activation in renal fibrosis in the unilateral ureteral obstruction (UUO) model. Obstructed kidneys from beta6(-/-) 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-beta1 mRNA levels and lower collagen content. Infusion with either angiotensin II (Ang II) or aldosterone (Aldo) or combination in beta6(-/-) UUO mice significantly increased collagen contents to levels comparable to those in identically treated WT. Active TGF-beta protein expression in beta6(-/-) mice was less in UUO kidneys with or without Ang II infusion compared to matched WT mice. Activated Smad 2 levels in beta6(-/-) obstructed kidneys were lower than in WT UUO mice, and did not increase when fibrosis was induced in beta6(-/-) UUO mice by Ang II infusion. Anti-TGF-beta antibody only partially decreased this Ang II-stimulated fibrosis in beta6(-/-) UUO kidneys. In situ hybridization and immunostaining showed low expression of PAI-1 mRNA and protein in tubular epithelium in beta6(-/-) UUO kidneys, with increased PAI-1 expression in response to Ang II, Aldo, or both. Our results indicate that interruption of alphavbeta6-mediated activation of TGF-beta1 can protect against tubulointerstitial fibrosis. Further, the robust induction of tubulointerstitial fibrosis without increase in activated Smad 2 levels in obstructed beta6(-/-) mice by Ang II suggests the existence of a TGF-beta1-independent pathway of induction of fibrosis through angiotensin.

MeSH Terms (22)

Aldosterone Animals Antigens, Neoplasm Blood Pressure DNA-Binding Proteins Fibrosis Integrins Kidney Diseases Kidney Tubules Male Mice Mice, Knockout Plasminogen Activator Inhibitor 1 Renin-Angiotensin System Smad2 Protein Systole Thrombospondin 1 Tissue Distribution Trans-Activators Transforming Growth Factor beta Transforming Growth Factor beta1 Ureteral Obstruction

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