title: Bcl-2 protects tubular epithelial cells from ischemia/reperfusion injury by dual mechanisms.
abstract: Ischemia/reperfusion (I/R) injury, which induces extensive loss of tubular epithelial cells, is associated with delayed graft function following kidney transplantation. Recent reports have suggested that cell death by I/R injury occurs by autophagy, a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, as well as by apoptosis. Recently, we demonstrated that overexpression of the anti-apoptotic factor, Bcl-2, inhibited tubular apoptosis and subsequent tubulointerstitial damage after I/R injury. Autophagy is also observed in cells undergoing cell death in several diseases. Therefore, we hypothesized that increased Bcl-2 protein may protect tubular epithelial cells by suppressing autophagy and inhibiting apoptosis. In the present study, a transgenic mouse model (LC3-GFP TG) in which autophagosomes are labeled with LC3-GFP and Bcl-2/LC3-GFP double transgenic mice (Bcl-2/LC3-GFP TG) were used to examine the effect of Bcl-2 on I/R-induced autophagy. I/R injury, which is associated with marked disruption of normal tubular morphology, promoted the formation of LC3-GFP dots, representing extensively induced autophagosomes. On electron microscopy, the autophagosomes contained mitochondria in I/R-injured tubular epithelial cells. In contrast, Bcl-2 augmentation suppressed the formation of autophagosomes and there was less tubular damage. In conclusion, Bcl-2 augmentation protected renal tubular epithelial cells from I/R injury by suppressing autophagosomal degradation and inhibiting tubular apoptosis.
authors.affiliation: Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Isaka
authors.forename: C
authors.initials: C
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Abe
authors.forename: M
authors.initials: M
authors.lastname: Okumi
authors.forename: N
authors.initials: N
authors.lastname: Ichimaru
authors.forename: R
authors.initials: R
authors.lastname: Imamura
authors.forename: Y
authors.initials: Y
authors.lastname: Kakuta
authors.forename: I
authors.initials: I
authors.lastname: Matsui
authors.forename: Y
authors.initials: Y
authors.lastname: Takabatake
authors.forename: H
authors.initials: H
authors.lastname: Rakugi
authors.forename: S
authors.initials: S
authors.lastname: Shimizu
authors.forename: S
authors.initials: S
authors.lastname: Takahara
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D017930:Genes, Reporter; D019254:Genes, bcl-2; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000627:therapeutic use; D011770:Pyruvate Kinase / Q000235:genetics; D051381:Rats; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D011770:Pyruvate Kinase