Smads as therapeutic targets for chronic kidney disease

Abstract

Renal fibrosis is a hallmark of chronic kidney disease (CKD). It is generally thought that transforming growth factor-β1 (TGF-β1) is a key mediator of fibrosis and mediates renal scarring positively by Smad2 and Smad3, but negatively by Smad7. Our recent studies found that in CKD, TGF-β1 is not a sole molecule to activate Smads. Many mediators such as angiotensin II and advanced glycation end products can also activate Smads via both TGF-β-dependent and independent mechanisms. In addition, Smads can interact with other signaling pathways, such as the mitogen-activated protein kinase and nuclear factor-kappaB (NF-κB) pathways, to regulate renal inflammation and fibrosis. In CKD, Smad2 and Smad3 are highly activated, while Smad7 is reduced or lost. In the context of fibrosis, Smad3 is pathogenic and mediates renal fibrosis by upregulating miR-21 and miR-192, but down-regulating miR-29 and miR-200 families. By contrast, Smad2 and Smad7 are protective. Overexpression of Smad7 inhibits both Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation. Interestingly, Smad4 has diverse roles in renal fibrosis and inflammation. The complexity and distinct roles of individual Smads in CKD suggest that treatment of CKD should aim to correct the imbalance of Smad signaling or target the Smad3-dependent genes related to fibrosis, rather than to block the general effect of TGF-β1. Thus, treatment of CKD by overexpression of Smad7 or targeting Smad3-dependent miRNAs such as downregulation of miR-21 or overexpression of miR-29 may represent novel therapeutic strategies for CKD.

Keywords: Chronic kidney disease; Fibrosis; Gene therapy; Inflammation; MicroRNA; TGF-β/Smads.

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. Red arrow lines (symbols) indicate positive regulation and blue lines (symbols) indicate negative regulation. AGE, advanced glycation end-products; Ang II, angiotensin II; ERK, extracellular-signal-regulated kinases; IkBa, IκBα; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-kappaB; TGF-β, transforming growth factor-β. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Figure 2

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. Thus, overexpression of miR-29 or miR-200 or knockdown of miR-21 and miR-192 may represent novel and specific therapeutic strategies for renal fibrosis. Red arrow lines (symbols) indicate positive regulation and blue lines (symbols) indicate negative regulation. TGF-β, transforming growth factor-β. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)