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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/F118    most recent 00021.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Huang, X. R. Articles by Lan, H. Y. Search for Related Content PubMed PubMed Citation Articles by Huang, X. R. Articles by Lan, H. Y.

Mice overexpressing latent TGF-β1 are protected against renal fibrosis in obstructive kidney disease

¹Department of Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China; and ²Department of Dermatology, Oregon Health and Science University, Portland, Oregon

Submitted 13 January 2008 ; accepted in final form 23 April 2008

Transforming growth factor (TGF)-β1, once activated, binds to its receptors and mediates renal fibrosis via the downstream Smad signaling pathway. We reported here that mice overexpressing latent TGF-β1 in keratinocytes were protected against renal fibrosis in a model of obstructive kidney disease. In normal mice, both transgenic (Tg) and wild-type (WT) mice had normal renal histology and function, despite a 10-fold increase in plasma latent TGF-β1 in Tg mice. A severe renal fibrosis was developed in WT mice at 7 days after urinary obstruction. Unexpectedly, renal fibrosis was prevented in Tg mice, although levels of latent TGF-β1 in both circulation and renal tissues remained high. Compared with the WT mice, quantitative real-time PCR showed that upregulation of renal -smooth muscle actin (SMA), collagen I, and collagen III mRNA was inhibited in Tg mice (60–70% reduced, all P < 0.01). These were further confirmed by immunohistochemistry with a marked inhibition of tubulointerstitial accumulation of -SMA+ fibroblasts, collagen I, and collagen III matrix in Tg mice (all P < 0.001). Further studies showed that inhibition of renal fibrosis in Tg mice was associated with a significant reduction in renal TGF-β1 and CTGF (60% reduced, P < 0.05), an increase in renal Smad7, a suppression of TSP-1 (a critical factor for TGF-β1 activation), and an inhibition of Smad2/3 activation (all P < 0.001). In conclusion, latent TGF-β may play a protective role in renal fibrosis. Inhibition of renal TGF-β1 expression and activation, thereby blocking the downstream TGF-β signaling pathway, may be a critical mechanism by which latent TGF-β1 protects against renal fibrosis.

TGF-β signaling; transgenic mice; Smads; UUO