Distinct roles of Smads and microRNAs in TGF-β signaling during kidney diseases

SummaryChronic kidney disease (CKD) is known to be the hallmark with fibrosis and inflammation that leads to end stage renal disease. Since the discovery over 2 decades ago of transforming growth factor (TGF)-β as a key mediator in CKD, studies of TGF-β signaling in the kidney have focused on fibrosis and inflammation. TGF-β exerts its cellular effect via Smad2 and Smad3 after binding to its receptors. Smad7, as an inhibitory Smad, provides a negative feedback loop to limit TGF-β action for maintaining homeostasis. Recently, the precise roles of individual Smads and receptors have been further characterized and the results reveal the complexity of TGF-β signaling during CKD. Although Smad3 plays a pathogenic role in CKD, Smad2 and Smad7 are protective. Furthermore, Smad4 enhances Smad3-mediated renal fibrosis as well as suppresses nuclear factor–κB-driven renal inflammation in a Smad7-dependent manner. Emerging evidence demonstrates the ability of TGF-β/Smad3 signaling to regulate specific microRNAs, revealing that microRNAs are critical downstream effectors of TGF-β/Smad3 signaling in renal fibrosis and inflammation. Recent studies in animal models of kidney disease demonstrate the therapeutic potential of microRNA therapy, Smad3 inhibitor, and Smad7 agonist in CKD. Because the accumulation of extracellular matrix and infiltration of inflammatory cells, which are the major pathological consequences of CKD, are due to activation of TGF-β/Smad3 signaling pathways, targeting the downstream TGF-β/Smad3 signaling pathway by gene transfer of either Smad7 or Smad3-dependent microRNAs, and by applying Smad3 inhibitor and Smad7 agonist may offer a specific and effective therapeutic strategy for kidney disease.

纖維化及炎癥是慢性腎病(CKD)的主要病理變化，最終導致終末期腎病。自從在二十多年前TGF-β被發現為CKD的關鍵中介物起，腎臟TGF-β訊息傳遞的相關研究便著眼於纖維化及炎癥方面。TGF-β在與受體結合後，透過Smad2及Smad3以產生細胞效應。具抑制性的Smad7可透過負回饋機制，以限制TGF-β的作用，從而維持平衡狀態。近年的研究更確認了個別Smads及受體的具體角色，顯示了CKD的TGF-β訊息傳遞複雜性。Smad3在CKD中具有致病角色，Smad2及Smad7則具保護性。再者，Smad4可促進Smad3介導的腎纖維化，并通過Smad7依賴的方式抑制NF-κB介導的腎臟炎癥。新證據更顯示，TGF-β/Smad3 訊息傳遞具調節特定microRNAs的能力，意味著microRNAs在腎纖維化及炎癥的TGF-β/Smad3訊息傳遞中是重要的下游效應物。近年關於腎病的動物實驗更發現，microRNA療法、Smad3抑制劑、及Smad7作用劑對CKD具潛在療效。有鑑於CKD的主要病理變化，如細胞外基質(ECM)的積聚及炎性細胞的浸潤，乃歸因於TGF-β/Smad3訊息傳遞途徑的活化，我們可以透過Smad7-或Smad3-倚賴性microRNAs的基因轉移、及採用Smad3抑制劑或Smad7作用劑等，對TGF-β/Smad3的下游訊息傳遞途徑作出干預，從而為腎病患者提供一個特定且有效的治療方案。