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Review
. 2016 Apr 1;310(7):F596-F606.
doi: 10.1152/ajprenal.00365.2015. Epub 2016 Jan 6.

TGF-β signaling in the kidney: profibrotic and protective effects

Affiliations
Review

TGF-β signaling in the kidney: profibrotic and protective effects

Angara Sureshbabu et al. Am J Physiol Renal Physiol. .

Abstract

Transforming growth factor-β (TGF-β) is generally considered as a central mediator of fibrotic diseases. Indeed, much focus has been placed on inhibiting TGF-β and its downstream targets as ideal therapeutic strategies. However, pharmacological blockade of TGF-β has not yet translated into successful therapy for humans, which may be due to pleiotropic effects of TGF-β signaling. Equally, TGF-β signaling as a protective response in kidney injury has been relatively underexplored. An emerging body of evidence from experimental kidney disease models indicates multifunctionality of TGF-β capable of inducing profibrotic and protective effects. This review discusses recent advances highlighting the diverse roles of TGF-β in promoting not only renal fibrosis but also protective responses of TGF-β signaling. We review, in particular, growing evidence that supports protective effects of TGF-β by mechanisms which include inhibiting inflammation and induction of autophagy. Additional detailed studies are required to fully understand the diverse mechanisms of TGF-β actions in renal fibrosis and inflammation that will likely direct toward effective antifibrotic therapies.

Keywords: BMP; Smad; TGF-β; apoptosis; autophagy; fibrosis; inflammation; kidney.

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Figures

Fig. 1.
Fig. 1.
Smad and non-Smad transforming growth factor-β1 (TGF-β1) signaling pathways. A: TGF-β1 activation occurs with the release from latent TGF-β binding protein (LTBP) complex by proteases. TGF-β1 signaling is initiated upon binding of active TGF-β1 with TGF-β receptor type II (TβRII) and forming the TβRI-TβRII heteromeric complex, leading to phosphorylation of Smad2/3, oligomerization with Smad4, and subsequent nuclear translocation to regulate the transcription of ECM genes. Smad7 serves as a negative regulator of TGF-β1 signaling. TGF-β1 also activates Smad-independent signaling such as the MAPK, mediated by the Ras-Raf-MEK-ERK pathway, and TGF-β-activated kinase 1 (TAK1), mediated by the TAK1-TAK1-binding protein 1 (TAB1) pathway. TGF-β1-induced TAK1 activation leads to signaling via MKK4-JNK and MKK3-p38 pathways and activation of transcription factors activator protein-1 (AP-1) and activating transcription factor 2 (ATF-2), respectively, and activation of NF-κB to mediate profibrotic responses.
Fig. 2.
Fig. 2.
An overview of Smad signaling and inflammatory pathways of TGF-β1 signaling. Binding of Smad4 to phosphorylated Smad2/3 leads to the nuclear translocation of the Smad complex to regulate gene transcription, including Smad7. Smad7 induces IκBα expression, which inhibits phosphorylation of p65/p50 proteins of the NF-κB signaling complex to prevent NF-κB-driven renal inflammation.
Fig. 3.
Fig. 3.
An overview of profibrotic and protective pathways of TGF-β1 signaling. Activation of TGF-β1 in response to kidney injury can signal both profibrotic and protective effects via Smad and non-Smad signaling pathways. Overexpression of Smad2 attenuates TGF-β1-induced Smad3 phosphorylation and type I collagen (Col-1α1) expression, whereas inhibition of Smad2 promotes renal fibrosis via enhanced TGF-β1/Smad3 signaling. TGF-β1-induced autophagy negatively regulates TGF-β1-stimulated collagen accumulation in the kidney by promoting collagen degradation. Autophagy also negatively regulates mature TGF-β1 expression, thereby protecting against kidney fibrosis.

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