Transglutaminase 2 gene ablation protects against renal ischemic injury by blocking constant NF-κB activation

Transglutaminase 2 knockout (TGase2−/−) mice show significantly reduced inflammation with decreased myofibroblasts in a unilateral ureteral obstruction (UUO) model, but the mechanism remains to be clarified. Nuclear factor-κB (NF-κB) activation plays a major role in the progression of inflammation in an obstructive nephropathy model. However, the key factors extending the duration of NF-κB activation in UUO are not known. In several inflammatory diseases, we and others recently found that TGase 2 plays a key role in extending NF-κB activation, which contributes to the pathogenesis of disease. In the current study, we found that NF-κB activity in mouse embryogenic fibroblasts (MEFs) from TGase2−/− mice remained at the control level while the NF-κB activity of wild-type (WT) MEFs was highly increased under hypoxic stress. Using the obstructive nephropathy model, we found that NF-κB activity remained at the control level in TGase2−/− mouse kidney tissues, as measured by COX-2 expression, but was highly increased in WT tissues. We conclude that TGase 2 gene ablation reduces the duration of NF-κB activation in ischemic injury.

Research highlights
► No acute renal tubular necrotic lesions were found in TGase2−/− mice with ischemic kidney injury.
► NF-κB activation is reduced in TGase2−/− mice with ischemic kidney injury.
► Hypoxic stress did not increase NF-κB activity in MEFs from TGase2−/− mice.
► COX-2 induction is suppressed in TGase2−/− mice with ischemic kidney injury.