期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 163, 期 4, 页码 1261-1273出版社
AMER SOC INVESTIGATIVE PATHOLOGY, INC
DOI: 10.1016/S0002-9440(10)63486-4
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资金
- NHLBI NIH HHS [HL53949, R37 HL053949, R01 HL053949] Funding Source: Medline
- NIA NIH HHS [R01 AG006528] Funding Source: Medline
- NIDDK NIH HHS [DK56942, P50 DK044757, DK44757, R01 DK056942] Funding Source: Medline
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-mill. 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 H (Ang H) 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 H 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 alpha6(-/-) UUO mice by Ang H infusion. Anti-TGF-beta antibody only partially decreased this Ang U-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 PAL I expression in response to Ang H, 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 H suggests the existence of a TGF-beta1-independent pathway of induction of fibrosis through angiotensin.
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