Journal
JOURNAL OF PATHOLOGY
Volume 227, Issue 2, Pages 175-188Publisher
WILEY
DOI: 10.1002/path.3976
Keywords
TGF-ss receptor II; Smad; renal inflammation; renal fibrosis
Funding
- Council of Hong Kong SAR [GRF 469110, CRF CUHK5/CRF/09]
- Focused Investment Scheme B from the Chinese University of Hong Kong [1902061]
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TGF-beta 1 binds receptor II (T beta RII) to exert its biological activities but its functional importance in kidney diseases remains largely unclear. In the present study, we hypothesized that T beta RII may function to initiate the downstream TGF-beta signalling and determine the diverse role of TGF-beta 1 in kidney injury. The hypothesis was examined in a model of unilateral ureteral obstructive (UUO) nephropathy and in kidney fibroblasts and tubular epithelial cells in which the T beta RII was deleted conditionally. We found that disruption of T beta RII inhibited severe tubulointerstitial fibrosis in the UUO kidney, which was associated with the impairment of TGF-beta/Smad3 signalling, but not with the ERK/p38 MAP kinase pathway. In contrast, deletion of T beta RII enhanced NF-B-K signalling and renal inflammation including up-regulation of Il-1 beta and Tnf alpha in the UUO kidney. Similarly, in vitro disruption of T beta RII from kidney fibroblasts or tubular epithelial cells inhibited TGF-beta 1-induced Smad signalling and fibrosis but impaired the anti-inflammatory effect of TGF-beta 1 on IL-1 beta-stimulated NF-B-K activation and pro-inflammatory cytokine expression. In conclusion, T beta RII plays an important but diverse role in regulating renal fibrosis and inflammation. Impaired TGF-beta/Smad3, but not the non-canonical TGF-beta signalling pathway, may be a key mechanism by which disruption of T beta RII protects against renal fibrosis. In addition, deletion of T beta RII also enhances NF-B-K signalling along with up-regulation of renal pro-inflammatory cytokines, which may be associated with the impairment of anti-inflammatory properties of TGF-beta 1. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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