Diverse Role of TGF-β in Kidney Disease

Inflammation and fibrosis are two key pathological features of chronic kidney disease (CKD). Excessive renal inflammation leads to progressive renal fibrosis, which eventually results in the end-stage renal disease (ESRD). Transforming growth factor-β (TGF-β) has been considered as a master regulator that diversely regulates inflammation and fibrosis via both canonical and non-canonical signaling pathways. In the context of renal fibrosis, TGF-β1 is pathogenic. In contrast, TGF-β is also a potent anti-inflammatory cytokine that functions to regulate immune response on both immune cells and intrinsic kidney cells. Thus, generally blocking TGF-β signaling inhibits renal fibrosis but promotes renal inflammation. Mechanistically, TGF-β1 may activate its downstream signaling molecule Smad3 to transcriptionally and differentially regulate renal inflammation and fibrosis via Smad3-dependent non-coding RNAs, including miRNAs and l¬¬ncRNAs, which are negatively regulated by Smad7. All these findings underly the complexity of TGF-β1 in renal inflammation and fibrosis. Thus, treatment of renal fibrosis and inflammation by specifically targeting Smad3 and Smad3-dependent non-coding RNAs or by overexpressing Smad7 have been developed. In this review, the paradoxical functions and underlying mechanisms of TGF-β1 in diversely regulating renal inflammation and fibrosis are discussed and novel therapeutic strategies for kidney disease by targeting downstream TGF-β/Smad signaling and transcriptomes are highlighted.