TRPM2 Calcium Channels as Mediators of Ischemia- Reperfusion Injury in the Mouse Liver.

Kingma, K. (Kyra) (2013) TRPM2 Calcium Channels as Mediators of Ischemia- Reperfusion Injury in the Mouse Liver. thesis, Medicine.

Text KingmaKD.pdf Restricted to Registered users only Download (740kB)

Abstract

Background: Ischemia reperfusion (IR) injury is a well-known clinical problem that occurs after liver transplantation, partial hepatic resection or trauma. IR injury causes hepatic cell damage and causes graft failure. Reducing IR injury will contribute to a better outcome of liver transplantation and liver surgery in general. Unfortunately the mechanism responsible for IR injury-induced cell damage is not fully understood. Ca2+ entry into the hepatocyte plays a significant role in cell death during IR injury. The nature of the calcium channel responsible for this influx of Ca2+ is unknown. A possible responsible channel is the Transient Receptor Potential Melastatine 2 (TRPM2) channel, a non-selective cation channel in the plasma membrane. Activation of TRPM2, in oxidative stress, mediates the influx of Ca2+ and Na+ into the cell. The aim of this study was to test whether TRPM2 channels play an important role in liver IR injury, using TRPM2 knock out (KO) mice. Methods: A mouse model of segmented (70%) hepatic ischemia and reperfusion was used to determine the role of TRPM2 in mediating cell death during IR injury. TRPM2 KO (n= 5) and Heterozygote (Het) (n=6) mouse livers were subjected to 45 minutes of ischemia and 24 hours of reperfusion. Two control groups underwent a sham procedure. After 24 hours of recovery, plasma liver marker enzymes and H and E histology sections were analysed for the extent and degree of liver damage. Results: IR injury increased liver enzyme markers. However the increase in the Het clamped group was much greater than the increase in the KO clamped group. Alanine aminotransferase (ALT) was 2.5 times greater in the Het clamped group (P=0.00). The mean asparate aminotransferase (AST) in the Het clamped group was 2778 ± 888 U/L in contrast to a mean of 704 ± 242 in the KO clamped group (P=0.04). Lactate dehydrogenase (LDH) levels showed a non-significant trend, with a 2.5 greater increase in the Het clamped group compared to the KO clamped group. Examination of the H and E histology sections showed that the percentage of necrosis in the TRPM2 KO group was substantially, approximately 30% less in the TRPM2 KO group after IR injury in contrast to the Het group (P=0.003). These results show that the TRPM2 KO mice endured significantly less liver damage after IR injury. And so, this experiment suggests that in the absence of TRPM2 the mouse liver is partially protected against IR injury. Conclusion: Plasma membrane TRPM2 non-selective calcium channels play an important role in liver IR injury.

Item Type:	Thesis (Thesis)
Supervisor name:	Faber, Klaas Nico
Supervisor name:	Barritt, Greg and Flinders University and School of Medicine Adelaide and Australia
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:53
Last Modified:	25 Jun 2020 10:53
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/1422

Actions (login required)

View Item