Expression of transforming growth factor-beta1 limits renal ischemia-reperfusion injury.
BACKGROUND
Renal ischemia-reperfusion injury (IRI) largely contributes to kidney transplant dysfunction and acute kidney injury, but its pathogenesis is not fully understood. In this study, the role of transforming growth factor (TGF)-beta1 in renal IRI is investigated using TGF-beta1 deficient mice.


METHODS
Human renal tubular epithelial cells (TEC) line (HK-2) was used as an in vitro model, and cell apoptosis was determined by flow cytometric analysis. Renal IRI was induced in mice by clamping renal vein and artery for 45 min at 32 degrees C.


RESULTS
Here, we showed that in cultures of HK-2 cells, TGF-beta1 expression was up-regulated by tumor necrosis factor (TNF)-alpha. Neutralization of TGF-beta1 activity increased both spontaneous and TNF-alpha-mediated apoptosis, and knockdown of TGF-beta1 expression increased the sensitivity of cell apoptosis to TNF-alpha. In a mouse model of renal IRI, a deficiency in TGF-beta1 expression increased the severity of renal injury, as indicated by more severe renal tubular damage, higher levels of serum creatinine or blood urea nitrogen in TGF-beta1 deficient mice as compared with those in wild-type controls. Further experiments showed that the antiapoptosis of TGF-beta1 correlated with up-regulation of Bcl-2 in kidney cells.


CONCLUSIONS
Expression of TGF-beta1 in TECs, potentially induced by proinflammatory TNF-alpha, renders TECs resistance to cell death. In mice, TGF-beta1 deficiency results in more prone to IRI. These data imply that TGF-beta1 may act as a feedback survival factor in the resistance to kidney injury and maintenance of epithelium homeostasis.
Guan
Qiunong
Q
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Nguan
Christopher Y C
CY
Du
Caigan
C
D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000172:deficiency; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D019254:Genes, bcl-2; D006801:Humans; D007668:Kidney / Q000293:injuries / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D015427:Reperfusion Injury / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
D017931:DNA Primers; D004268:DNA-Binding Proteins; D035683:MicroRNAs; C499308:Rag2 protein, mouse; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha