Diverse roles of TGF-β/Smads in renal fibrosis and inflammation

Abstract

TGF-β1 has been long considered as a key mediator in renal fibrosis and induces renal scarring largely by activating its downstream Smad signaling pathway. Interestingly, while mice overexpressing active TGF-β1 develop progressive renal injury, latent TGF-β1 plays a protective role in renal fibrosis and inflammation. Under disease conditions, Smad2 and Smad3 are highly activated, while Smad7 is degraded through the ubiquitin proteasome degradation mechanism. In addition to TGF-β1, many pathogenic mediators such as angiotensin II and advanced glycation end products can also activate the Smad pathway via both TGF-β-dependent and independent mechanisms. Smads interact with other signaling pathways, such as the MAPK and NF-κB pathways, to positively or negatively regulate renal inflammation and fibrosis. Studies from gene knockout mice demonstrate that TGF-β1 acts by stimulating its downstream Smads to diversely regulate kidney injury. In the context of renal fibrosis and inflammation, Smad3 is pathogenic, while Smad2 and Smad7 are protective. Smad4 exerts its diverse roles by transcriptionally enhancing Smad3-mediated renal fibrosis while inhibiting NF-κB-driven renal inflammation via a Smad7-dependent mechanism. Furthermore, we also demonstrated that TGF-β1 acts by stimulating Smad3 to positively or negatively regulate microRNAs to exert its fibrotic role in kidney disease. In conclusion, TGF-β/Smad signaling is a major pathway leading to kidney disease. Smad3 is a key mediator in renal fibrosis and inflammation, whereas Smad2 and Smad7 are renoprotective. Smad4 exerts its diverse role in promoting renal fibrosis while inhibiting inflammation. Thus, targeting the downstream TGF-β/Smad3 signaling pathway by gene transfer of either Smad7 or Smad3-dependent microRNAs may represent a specific and effective therapeutic strategy for kidney disease.

Keywords: TGF-β/Smads; anti-TGF-β therapy; fibrosis; inflammation; microRNAs..

Figure 1

TGF-β/Smads and crosstalk pathways in renal fibrosis and inflammation. After binding to TβRII, TGF-β1 activates the TβRI-kinase which phosphorylates Smad2 and Smad3. The phosphorylated Smad2 and Smad3 then bind to Smad4 and form the Smad complex, which translocates into the nucleus and regulates the target gene transcription, including Smad7. Smad7 is an inhibitory Smad that functions to block Smad2/3 activation by degrading the TβRI and Smads and to inhibit NF-κB-driven inflammatory response by inducing IκBα, an inhibitor of NF-κB. Note that Ang II and AGEs can activate Smads independent of TGF-β1 via the ERK/p38/MAPK crosstalk pathway. Blue lines (symbols) indicate protective or negative regulation pathways, while red arrows (symbols) represent pathogenic or positive regulation pathways.

Figure 2

Protective role of Smad2 in renal fibrosis. Smad2 physically binds Smad3 but prevents Smad3 from activation through two possible mechanisms: 1) competitively inhibit Smad3 binding to the TβRI for phosphorylation; 2) block phosphorylated Smad3 nuclear translocation and binding to the DNA sequences, therefore inhibiting Smad3-mediated renal fibrosis. Blue lines (symbols) indicate protective or negative regulation pathways, while red arrows (symbols) represent pathogenic or positive regulation pathways.

Figure 3

Diverse roles of Smad4 in renal fibrosis and inflammation. Smad4 binds phosphorylated Smad2/Smad3 to form the Smad complex that translocates into the nucleus to regulate target genes related to fibrogenesis including Smad7. Upregulation of Smad7 prevents NF-κB/p50/p65 from phosphorylation and nuclear translocation by inducing IκBα expression. Therefore, Smad4 acts as a fine turner to promote Smad3-mediated fibrosis while inhibiting NF-κB-driven inflammation. Blue lines (symbols) indicate protective or negative regulation pathways, while red arrows (symbols) represent pathogenic or positive regulation pathways.

Figure 4

Inhibitory role of Smad7 in renal fibrosis and inflammation. Overexpression of Smad7 prevents Smad2/3 from phosphorylation by degrading the TβRI as well as Smads via the ubiquitin degradation pathway (Ub), thereby inhibiting Smad3-dependent renal fibrosis in response to TGF-β1, AGEs, and angiotensin II (Ang II). In addition, overexpression of Smad7 can induce IκBα, an inhibitor of KF-κB, therefore inhibiting NF-κB-driven renal inflammation. Thus, Smad7 acts as a therapeutic agent for treatment of kidney diseases. Blue lines (symbols) indicate protective or negative regulation pathways, while red arrows (symbols) represent pathogenic or positive regulation pathways.

Figure 5

Smad3-dependent miRNAs in renal fibrosis. TGF-β1 acts by stimulating Smad3 to positively regulate miR-21 and miR-192, but negatively regulate the miR-29 or miR-200 families, to mediate renal fibrosis. Blue lines (symbols) indicate protective or negative regulation pathways, while red arrows (symbols) represent pathogenic or positive regulation pathways.