Signaling Mechanism of TGF-1 in Prevention of Renal
Inflammation: Role of Smad7
Wansheng Wang,* Xiao R. Huang,* Allen G. Li,
†
Fang Liu,* Jin-Hua Li,* Luan D. Truong,*
‡
Xiao J. Wang,
†
and Hui Y. Lan*
*Departments of Medicine and Pathology, Baylor College of Medicine, Houston, Texas;
†
Department of Dermatology,
Oregon Health & Science University, Portland, Oregon; and
‡
Department of Pathology, The Methodist Hospital,
Houston, Texas
TGF- has been shown to play a critical role in anti-inflammation; however, the signaling mechanisms of TGF- in
anti-inflammatory response remains largely unclear. This study reported that mice that overexpress latent TGF-1 on skin are
protected against renal inflammation in a model of obstructive kidney disease and investigated the signaling mechanism of
TGF-1 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-1, TNF-, 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-1 in circulation (a 10-fold increase) and renal tissues (a
2.5-fold increase). Further studies showed that inhibition of renal inflammation in TGF-1 transgenic mice was also associated
with a marked upregulation of renal Smad7 and IB and a suppression of NF-B activation in the diseased kidney (all P <
0.01). These in vivo findings suggested the importance of TGF-–NF-B 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 IB directly in a time- and dose-dependent manner, thereby inhibiting NF-B activation and
NF-B– driven inflammatory response. In conclusion, latent TGF- may have protective roles in renal inflammation. Smad7-
mediated inhibition of NF-B activation via the induction of IkB may be the central mechanism by which latent TGF-
prevents renal inflammation.
J Am Soc Nephrol 16: 1371–1383, 2005. doi: 10.1681/ASN.2004121070
T
he TGF- family, including TGF-1, TGF-2, and TGF-
3, is a group of pleiotropic secreted cytokines with
unique and potent anti-inflammatory and immuno-
regulatory properties (1). They have a broad spectrum of bio-
logic functions and act on a large variety of cell types. Several
experimental and human studies reveal an important role for
TGF- in renal fibrosis (2), which is crucial for the progression
to ESRD. Mice with overexpression of active TGF-1 develop
severe renal damage with progressive renal fibrosis (3). It is
interesting that blockade of TGF- by anti–TGF- antibodies
alleviates renal fibrosis in diabetic nephropathy in mice and
puromycin aminonucleoside nephropathy in rats but worsens
albuminuria and proteinuria in these disease models (4,5), sug-
gesting a complex role of TGF-, beyond its profibrotic effects,
in the progression of renal diseases. We speculated that these
observations might be associated with protective roles of circu-
lating latent TGF- in renal inflammation. Thus, blockade of
circulating TGF- with a neutralizing TGF- antibody enhances
proteinuria in these disease models. However, there is lack of
evidence to support this hypothesis. The signaling mechanisms
that are responsible for the potential anti-inflammatory effects
of TGF- are yet largely unknown. Although the role of TGF-
in fibrosis has been firmly established, little attention has been
paid to the circulating levels of this cytokine in the disease
conditions. TGF- functions in both autocrine and paracrine
manners to regulate cell proliferation, apoptosis, differentia-
tion, chemotaxis, extracellular matrix production, cell migra-
tion, and immune response (6). Mice with targeted disruption
of TGF-1 display no gross abnormalities at birth but succumb
to wasting associated with multifocal inflammation at approx-
imately day 20 after birth (7). Systemic administration of TGF-
greatly alleviates the inflammatory response in streptococcus
cell wall–induced erosive arthritis and prevents the relapse of
autoimmune encephalomyelitis, insulitis, and systemic lupus
erythematosus in the MRL/lpr/lpr murine model (8 –11),
strongly suggesting the anti-inflammatory effect of circulating
TGF-.
Although it is known that TGF- plays an important role in
inflammatory responses, the underlying signaling mechanisms
by which TGF- exerts its anti-inflammatory function remain
largely unclear. Because mice that overexpress the bioactive
form of hepatic TGF-1 exhibit progressive renal injury associ-
ated with a highly increased circulating active TGF-1 (12), our
study sought to test the hypothesis that the increased circulat-
Received December 10, 2004. Accepted February 16, 2005.
Published online ahead of print. Publication date available at www.jasn.org.
Address correspondence to: Dr. Hui Y. Lan, Department of Medicine-Nephrol-
ogy, Baylor College of Medicine, One Baylor Plaza, Alkek N520, Houston, TX
77030. Phone: 713-798-1303; Fax: 713-798-5010; E-mail: hlan@bcm.tmc.edu
Copyright © 2005 by the American Society of Nephrology ISSN: 1046-6673/1605-1371