Transglutaminase-1 protects renal epithelial cells from hydrogen peroxide-induced apoptosis through activation of STAT3 and AKT signaling pathways.
Our recent studies showed that transglutaminase-1 (TGase-1) is uniquely expressed in mouse renal proximal tubular cells (RPTC) and mediates cell proliferation. In this study, we investigated the role of TGase-1 in cell survival and the survival signaling pathways regulated by TGase-1 in RPTC following oxidant injury. Exposure of RPTC to hydrogen peroxide (H2O2) resulted in apoptosis and an increase in TGase activity. Inhibition of TGase activity with monodansylcadervine (MDC), a TGase inhibitor, or knockdown of TGase-1 with small interference (si)RNA enhanced apoptosis and decreased cell survival in H2O2-treated RPTC. Conversely, overexpression of TGase-1 rendered RPTC more resistant to H2O2 toxicity and MDC treatment blocked this response. Concurrent with RPTC apoptosis, phosphorylation of AKT, signal transducer and activator of transcription-3 (STAT3), and glucogen synthase kinase-3beta (GSK-3beta) were observed. Pretreatment of cells with MDC or TGase-1 siRNA inhibited phosphorylation of all these molecules. Inhibition of either the AKT or STAT3 pathway potentiated H2O2-induced cell death and increased GSK-3beta activity by dephosphorylation at serine 9. Furthermore, treatment with GSK-3beta inhibitors reduced H2O2-induced apoptosis and abolished the death-promoting effect of AKT and STAT3 inhibition. Therefore, we have identified TGase-1 as a novel survival factor in renal epithelial cells and it contributes to cell survival through activation of the AKT and STAT3 signaling pathways following oxidant injury.
Ponnusamy
Murugavel
M
Department of Medicine, Brown University School of Medicine, Rhode Island Hospital, Providence, RI 02903, USA.
Pang
Maoyin
M
Annamaraju
Pavan Kumar
PK
Zhang
Zhu
Z
Gong
Rujun
R
Chin
Y Eugene
YE
Zhuang
Shougang
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D004847:Epithelial Cells / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000502:physiology; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D053614:Janus Kinase 2 / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000166:cytology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D016877:Oxidants / Q000633:toxicity*; D010957:Plasmids / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013778:Tetrazolium Salts; D013844:Thiazoles; D011503:Transglutaminases / Q000502:physiology*
D004396:Coloring Agents; D016877:Oxidants; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013778:Tetrazolium Salts; D013844:Thiazoles; D006861:Hydrogen Peroxide; D011503:Transglutaminases; C105804:transglutaminase 1; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C022616:thiazolyl blue