Signaling mechanism of TGF-β1 in prevention of renal inflammation: Role of Smad7

Wansheng Wang, Xiao R. Huang, Allen G. Li, Fang Liu, Jin Hua Li, Luan Truong, Xiao J. Wang, Hui Y. Lan

Research output: Contribution to journalArticle

187 Scopus citations

Abstract

TGF-β has been shown to play a critical role in anti-inflammation; however, the signaling mechanisms of TGF-β in anti-inflammatory response remains largely unclear. This study reported that mice that overexpress latent TGF-β1 on skin are protected against renal inflammation in a model of obstructive kidney disease and investigated the signaling mechanism of TGF-β1 in inhibition of renal inflammation in vivo and in vitro. Seven days after urinary obstruction, wild-type mice developed severe renal inflammation, including massive T cell and macrophage infiltration and marked upregulation of IL-1β, TNF-α, and intercellular adhesion molecule-1 (all P < 0.001). Surprising, renal inflammation was prevented in transgenic mice. This was associated with an increase in latent TGF-β1 in circulation (a 10-fold increase) and renal tissues (a 2.5-fold increase). Further studies showed that inhibition of renal inflammation in TGF-β1 transgenic mice was also associated with a marked upregulation of renal Smad7 and IκBα and a suppression of NF-κB activation in the diseased kidney (all P < 0.01). These in vivo findings suggested the importance of TGF-β-NF-κB cross-talk signaling pathway in regulating renal inflammation. This was tested in vitro in a doxycycline-regulated Smad7-expressing renal tubular cell line. Overexpression of Smad7 was able to upregulate IκBα directly in a time- and dose-dependent manner, thereby inhibiting NF-κB activation and NF-κB-driven inflammatory response. In conclusion, latent TGF-β may have protective roles in renal inflammation. Smad7-mediated inhibition of NF-κB activation via the induction of IkBα may be the central mechanism by which latent TGF-β prevents renal inflammation.

Original languageEnglish (US)
Pages (from-to)1371-1383
Number of pages13
JournalJournal of the American Society of Nephrology
Volume16
Issue number5
DOIs
StatePublished - 2005

ASJC Scopus subject areas

  • Nephrology

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