Thromboxane A (2) Synthase and Thromboxane Receptor Deletion Reduces Ischaemia/Reperfusion-Evoked Inflammation, Apoptosis, Autophagy and Pyroptosis

摘要

Aim Enhancement of thromboxane A (2) (TXA (2) ) synthase (TXAS) activity, TXA (2) release, and thromboxane prostanoid (TP) receptor activation leads to vasoconstriction and oxidative injury. We explored whether genetic deletion of TXAS/TXA (2) /TP signalling may reduce renal ischaemia/reperfusion (I/R) injury in mice. Materials and Methods Renal haemodynamics and function were evaluated in TXAS (+/+) TP (+/+) (wild-type, WT), TXAS (-/-) (TXS (-/-) ), TP (-/-) and TXAS (-/-) TP (-/-) (double knockout, dKO) mice in response to intravenous TXA (2) mimetic-U46619 and 45-minute renal ischaemia and 4-hour reperfusion injury. We examined renal TXAS and TP expression, blood urea nitrogen (BUN) and creatinine, reactive oxygen species (ROS) amount, pro-inflammatory cytokines and pathophysiologic mechanisms, including apoptosis, autophagy and pyroptosis under I/R injury. Results Renal I/R enhanced the levels of TXAS, TP, nuclear factor-kappa B, nicotinamide adenine dinucleotide phosphate oxidase gp91, Bax/Bcl-2/caspase-3/apoptosis, Beclin-1/LC3-II/autophagy, caspase-1/gasdermin D/interleukin-1 beta/pyroptosis, renal thromboxane B (2) (TXB (2) ) concentration, ROS amount, plasma BUN, creatinine and TXB (2) and decreased renal endothelial nitric oxide synthase expression in WT mice. All these enhanced parameters were significantly decreased in three KO mice. Intravenous U46619 significantly decreased renal microcirculation and enhanced gp91 and Bax/Bcl-2 in WT and TXS (-/-) but not TP (-/-) in dKO mice. I/R significantly decreased renal microcirculation in all mice; however, the time for recovery to baseline renal blood flow level was significantly shortened in TXS (-/-) , TP (-/-) and dKO mice versus WT mice. Blockade of TXAS/TP signalling attenuated I/R-enhanced pro-inflammatory cytokine profile. Conclusion Blockade of TXAS/TXA (2) /TP signalling confers renal protection against I/R injury through the actions of anti-oxidation, anti-inflammation, anti-apoptosis, anti-autophagy and anti-pyroptosis.