Smads as therapeutic targets for chronic kidney disease

다국어 초록 (Multilingual Abstract)

Renal fibrosis is a hallmark of chronic kidney disease (CKD). It is generally thought that transforming growth factor-b1 (TGF-b1) 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-b1 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-b-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-kB) 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-kB-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-b1. Thus, treatment of CKD by overexpression of Smad7 or targeting Smad3-dependent miRNAs such as downregulation of miR-21or overexpression of miR-29 may represent novel therapeutic strategies for CKD.

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