Short hairpin RNA modulates transforming growth factor beta signaling in life-threatening liver failure in mice.
OBJECTIVE
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.
Mizuguchi
Yoshiaki
Y
Department of Surgery for Organ Function and Biological Regulation, Nippon Medical School, Tokyo, Japan.
Yokomuro
Shigeki
S
Mishima
Takuya
T
Arima
Yasuo
Y
Shimizu
Tetsuya
T
Kawahigashi
Yutaka
Y
Kanda
Tomohiro
T
Yoshida
Hiroshi
H
Takizawa
Toshihiro
T
Tajiri
Takashi
T
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015316:Genetic Therapy / Q000379:methods*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006801:Humans; D017114:Liver Failure, Acute / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010957:Plasmids / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D034622:RNA Interference; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II