急性肾损伤（AKI）是一组以突发性肾功能下降为特征的临床综合征，但其机制未明确。TGF-β及下游Smad2/3决定肾纤维化进程，但在AKI中的作用却有争议。多数观点认为TGF-β保护AKI，但预实验发现敲除Smad3反而减轻AKI的肾损害且引起Smad2的过度激活，提示Smad2可能有不同于Smad3的功能。本课题组近期研究表明Smad2亦可负调控Smad3信号减轻肾纤维化。因此我们假设Smad2（而非Smad3）介导了TGF-β对AKI的保护作用。课题组拟在Smad2条件性敲除小鼠上诱导AKI模型，评估Smad2对肾功能的作用，同时检测其对炎症、凋亡等病理过程的调节及它与Smad3的相互调控，并与体外进一步探讨机制。综上所述，TGF-β下游通路的复杂性决定了它在AKI中的多重作用，因而剖析其下游Smad2和Smad3的功能及相互关系，有助于阐明AKI的发病机制并为药物设计提供新靶点。

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid loss of renal function, but the underlying mechanism is still obscure. It is well accepted that TGF-β/Smad signaling drives renal fibrosis, however, its function in AKI is still controversial. Despite the majority reported TGF-β1 as a protective molecule in AKI, our pilot study indicated that knockout of Smad3 did attenuate infiltration of inflammatory cells while ameliorating apoptosis of tubular epithelial cells (TEC) to prevent renal injury. It is noticeable that Smad2, another critical downstream of TGF-β1, was hyperactivated in S3KO injured kidney, with its function undetected. Considering our recent finding that Smad2 protected against renal fibrosis by negatively regulating the function of Smad3, we hypothesized that Smad2, rather than Smad3, may mediate the protective role of TGF-β in AKI. This hypothesis will be tested in vivo in Smad2 conditional knockout mice with cisplatin-induced AKI and in vitro in Smad2 knockdown/overexpression TECs in response to cisplatin and the underlying mechanism will be further detected. Collectively, dissection of downstream molecules of TGF-β will provide us an insight view on the physiopathology of acute kidney injury while indicating the potential therapeutic target for clinic use.