Short hairpin RNA modulates transforming growth factor beta signaling in life-threatening liver failure in mice.

BACKGROUND & AIMS: Transforming growth factor beta (TGF-beta) receptor II (TGF-betaRII), which is essential for TGF-beta 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-beta system. In the liver, TGF-beta plays an essential role in hepatocyte apoptosis, growth inhibition, and progression of fibrogenesis. There is a critical need to introduce technology involving the TGF-beta 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-betaRII, using hepatocyte injury in human and mouse cell lines and liver injury mouse models.

RESULTS

We demonstrated that short hairpin RNA targeting TGF-betaRII can be used to silence TGF-betaRII 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-betaRII protected mice from life-threatening acute liver failure.

CONCLUSIONS

Our study suggests the potential use of TGF-betaRII silencing by RNAi as an analytical tool for TGF-beta signaling and gene-specific therapy in human disorders.