Tissue Transglutaminase Contributes to Pro-Inflammatory Cytokine LIGHT-Induced Ang II Sensitization.

Hypertension is a severe cardiovascular complication with elevated inflammation and pressor sensitivity. Activated enzymatically and transcriptionally by inflammatory cytokines, tissue transglutaminase (TG2), a ubiquitous crosslinking enzyme, is known to stabilize the Ang II receptor AT1 and contribute to hypertension and cardio-renal syndrome.We hypothesized that TG2 play an essential role in the inflammation-induced Ang II sensitization in hypertension via its posttranslational modifications. To test this, we found a significant TG2-dependent increase in renal transglutaminase activity in animals infused with inflammatory cytokine LIGHT/TNFSF14 (4ng/day) for 14 days (PBS=0.5±0.04, LIGHT=0.8±0.03, LIGHT+TG2 inhibitor ERW1041E=0.6±0.05, LIGHT+TG2-/-=0.4±0.01mU/mg protein, n=4-5, p<0.05). Western blot further determined an ~9 fold increase in renal TG2 and ~4 fold in AT1 in animals infused with LIGHT only (n=3, p<0.05). Mutagenesis study on AT1 confirmed the requirement of TG2 modification in LIGHT-induced receptor accumulation. Following this, we identified an ~80% pronouncement in Ang II-induced calcium response in luciferase reporter cells co-treated with LIGHT but not LIGHT plus ERW1041E (n=3, p<0.01). Taken together, our studies may shed light on the intrinsic role of TG2 as the pressor sensitizer downstream of the cytokines. Our results could also be a proof of concept for the use of TG2 inhibitors as novel antihypertensives.