Investigation of renal ischemia-reperfusion induced liver injury
| dc.contributor.author | Shang, Yue | |
| dc.contributor.examiningcommittee | House, James (Food and Human Nutritional Science), Pierce, Grant (Physiology and Pathophysiology), Leung, Susan (Department of Pharmacology and Pharmacy, The University of Hong Kong) | en_US |
| dc.contributor.supervisor | O, Karmin (Animal Science) | en_US |
| dc.date.accessioned | 2018-09-11T15:51:54Z | |
| dc.date.available | 2018-09-11T15:51:54Z | |
| dc.date.issued | 2018-08 | en_US |
| dc.date.submitted | 2018-08-29T19:12:07Z | en |
| dc.degree.discipline | Animal Science | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Ischemia-reperfusion (IR) is a major cause of acute kidney injury (AKI). AKI is often associated with dysfunction of remote organs also known as distant organ injury. Previous clinical and animal studies have identified that oxidative stress and inflammation are main pathological components in renal IR injury. However, their roles and regulatory mechanisms in distant organs are not well understood. Liver is a key metabolic organ for redox balance, immune regulation and detoxification. Liver function is often compromised by AKI. The general objective of my research was to investigate the mechanism by which renal ischemia-reperfusion led to oxidative stress and inflammatory responses in the liver. The left kidney of Sprague-Dawley rats was subjected to 45min ischemia followed by 1h or 6h of reperfusion. Renal ischemia-reperfusion impaired kidney and liver function as indicated by increased plasma creatinine and aminotransferase levels. A decrease in glutathione level was observed in the liver and plasma, along with increased hepatic lipid peroxidation and plasma homocysteine levels, as indicators of oxidative stress. Renal ischemia-reperfusion caused a significant decrease in mRNA and protein levels of hepatic enzyme cystathionine gamma-lyase, which regulates the transsulfuration pathway. A decrease in gene expression of glutamate-cysteine ligase subunits for glutathione biosynthesis was mediated through inhibition of the transcription factor Nrf2. Renal IR also caused a significant increase in proinflammatory cytokine (MCP-1, TNF-α, IL-1beta and IL-6) protein levels in the liver, kidney and plasma. Activation of nuclear transcription factor kappa B (NF-kappaB) was detected in the liver at 1h and 6h after renal IR. This was accompanied with a significant increase in the mRNA levels of proinflammatory cytokines in the liver. An elevation of myeloperoxidase activity and inflammatory foci were detected in the liver at 6h after renal IR, indicating neutrophil infiltration. In conclusion, results from our research have demonstrated that renal IR can induce acute liver injury. We have identified that during renal IR, down-regulation of hepatic Nrf2/glutathione production and up-regulation of NF-kappaB/cytokine expression are responsible for increased oxidative stress and inflammatory response, which, in turn, exert detrimental effects to distant organs. | en_US |
| dc.description.note | October 2018 | en_US |
| dc.identifier.citation | Shang Y., Y. L. Siow, C. K. Isaak and K. O. 2016. Downregulation of glutathione biosynthesis contributes to oxidative stress and liver dysfunction in acute kidney injury. Oxidative Medicine and Cellular Longevity, 2016(10):1-13. | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/33298 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Acute kidney injury | en_US |
| dc.subject | Renal ischemia-reperfusion | en_US |
| dc.subject | Distant organ injury | en_US |
| dc.subject | Oxidative stress | en_US |
| dc.subject | Inflammation | en_US |
| dc.subject | Glutathione synthesis | en_US |
| dc.title | Investigation of renal ischemia-reperfusion induced liver injury | en_US |
| dc.type | doctoral thesis | en_US |