Short Hairpin RNA Modulates Transforming Growth Factor β Signaling in Life-Threatening Liver Failure in Mice

Background & Aims: Transforming growth factor β (TGF-β) receptor II (TGF-βRII), which is essential for TGF-β signaling and is involved in the causation or participates in the pathway of various human disorders, is consequently considered a key target for therapeutics and analysis of the pathophysiology associated with disruption of the TGF-β system. In the liver, TGF-β plays an essential role in hepatocyte apoptosis, growth inhibition, and progression of fibrogenesis. There is a critical need to introduce technology involving the TGF-β system, such as RNA interference (RNAi), which has high potential for in vivo therapeutics and analytical activities. Methods: Here, we investigated the effect of short hairpin RNA targeting TGF-βRII, using hepatocyte injury in human and mouse cell lines and liver injury mouse models. Results: We demonstrated that short hairpin RNA targeting TGF-βRII can be used to silence TGF-βRII genes in mouse and human cell lines, and physiologic and morphologic changes in hepatocytes suffering from acute injury are spared by RNAi-mediated gene silencing of the target gene and by suppressing downstream signal transduction. Furthermore, short hairpin RNA targeting TGF-βRII protected mice from life-threatening acute liver failure. Conclusions: Our study suggests the potential use of TGF-βRII silencing by RNAi as an analytical tool for TGF-β signaling and gene-specific therapy in human disorders.