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Thromb Haemost 2020; 120(02): 329-343
DOI: 10.1055/s-0039-3400304
Atherosclerosis and Ischaemic Disease
Georg Thieme Verlag KG Stuttgart · New York

Thromboxane A2 Synthase and Thromboxane Receptor Deletion Reduces Ischaemia/Reperfusion-Evoked Inflammation, Apoptosis, Autophagy and Pyroptosis

Tsung-Hung Chueh
1   Department of Life Science, School of Life Science, College of Science, National Taiwan Normal University, Taipei, Taiwan
,
Yu-Hsiuan Cheng
1   Department of Life Science, School of Life Science, College of Science, National Taiwan Normal University, Taipei, Taiwan
,
Kuo-Hsin Chen   *
2   Division of General Surgery, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan
3   Department of Electrical Engineering, Yuan Ze University, Taoyuan City, Taiwan
,
Chiang-Ting Chien   *
1   Department of Life Science, School of Life Science, College of Science, National Taiwan Normal University, Taipei, Taiwan
› Institutsangaben Funding This work was supported by grant MOST-102–2320-B-003–001-MY3 (to C.-T.C.) and a research fund from the Far-Eastern Memorial Hospital (to K.-H.C.).
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Publikationsverlauf

24. April 2019

03. Oktober 2019

Publikationsdatum:
30. November 2019 (online)

    Lizenzen und Reprints

Abstract

Aim Enhancement of thromboxane A2 (TXA2) synthase (TXAS) activity, TXA2 release, and thromboxane prostanoid (TP) receptor activation leads to vasoconstriction and oxidative injury. We explored whether genetic deletion of TXAS/TXA2/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 TXA2 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-κB, nicotinamide adenine dinucleotide phosphate oxidase gp91, Bax/Bcl-2/caspase-3/apoptosis, Beclin-1/LC3-II/autophagy, caspase-1/gasdermin D/interleukin-1β/pyroptosis, renal thromboxane B2 (TXB2) concentration, ROS amount, plasma BUN, creatinine and TXB2 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/TXA2/TP signalling confers renal protection against I/R injury through the actions of anti-oxidation, anti-inflammation, anti-apoptosis, anti-autophagy and anti-pyroptosis.

Keywords

apoptosis - autophagy - ischaemia/reperfusion - kidney - thromboxane A2 synthase - thromboxane prostanoid receptor - pyroptosis

Authors' Contributions

Research idea and study design: T.H.C., Y.H.C., K.H.C., C.T.C.; data acquisition: T.H.C., Y.H.C.; data analysis/interpretation: T.H.C., K.H.C., C.T.C.; statistical analysis: T.H.C., C.T.C.; supervision or mentorship: K.H.C., C.T.C. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.


* These senior authors contributed equally to this work.


Supplementary Material

 

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