TGF-β/Smad signaling in renal fibrosis

Abstract

TGF-β (transforming growth factor-β) is well identified as a central mediator in renal fibrosis. TGF-β initiates canonical and non-canonical pathways to exert multiple biological effects. Among them, Smad signaling is recognized as a major pathway of TGF-β signaling in progressive renal fibrosis. During fibrogenesis, Smad3 is highly activated, which is associated with the down-regulation of an inhibitory Smad7 via an ubiquitin E3-ligases-dependent degradation mechanism. The equilibrium shift between Smad3 and Smad7 leads to accumulation and activation of myofibroblasts, overproduction of ECM (extracellular matrix), and reduction in ECM degradation in the diseased kidney. Therefore, overexpression of Smad7 has been shown to be a therapeutic agent for renal fibrosis in various models of kidney diseases. In contrast, another downstream effecter of TGF-β/Smad signaling pathway, Smad2, exerts its renal protective role by counter-regulating the Smad3. Furthermore, recent studies demonstrated that Smad3 mediates renal fibrosis by down-regulating miR-29 and miR-200 but up-regulating miR-21 and miR-192. Thus, overexpression of miR-29 and miR-200 or down-regulation of miR-21 and miR-192 is capable of attenuating Smad3-mediated renal fibrosis in various mouse models of chronic kidney diseases (CKD). Taken together, TGF-β/Smad signaling plays an important role in renal fibrosis. Targeting TGF-β/Smad3 signaling may represent a specific and effective therapy for CKD associated with renal fibrosis.

Keywords: Smads mediators; TGF-ß; mechanisms; renal fibrosis; therapeutics.

Figure 1

Role of TGF-β/Smad signaling in kidney disease. TGF-β1 signals through the downstream mediators to exert its biological activities on different cell types of kidney cells during renal inflammation and fibrosis.

Figure 2

Regulation of TGF-β/Smad3 in fibrosis-related microRNAs during renal fibrosis. TGF-β1 activates Smad3 that binds directly to a number of microRNAs to either negatively or positively regulate their expression and function in renal fibrosis.

Figure 3

Potential therapeutic strategies for renal fibrosis by specifically targeting downstream TGF-β/Smad signaling. Since renal fibrosis is mediated positively by Smad3 but negatively by Smad7, treatment for renal fibrosis can target Smad3 with specific inhibitors or Smad3-dependent microRNAs that regulate fibrosis, and/or by promoting Smad7 with gene therapy or specific agonists.