Regulation of folate reabsorption and oxidative stress in acute kidney injury
| dc.contributor.author | Wijerathne, Charith Udara Bandara | |
| dc.contributor.examiningcommittee | House, James (Animal Science) | en_US |
| dc.contributor.examiningcommittee | Pierce, Grant (Physiology and Pathophysiology) | en_US |
| dc.contributor.examiningcommittee | Dhingra, Sanjiv (Physiology and Pathophysiology) | en_US |
| dc.contributor.examiningcommittee | Devlin, Angela (University of British Columbia) | en_US |
| dc.contributor.supervisor | O, Karmin | |
| dc.date.accessioned | 2023-04-12T16:44:46Z | |
| dc.date.available | 2023-04-12T16:44:46Z | |
| dc.date.copyright | 2023-04-12 | |
| dc.date.issued | 2023-03-27 | |
| dc.date.submitted | 2023-03-28T01:00:25Z | en_US |
| dc.date.submitted | 2023-04-12T16:18:58Z | en_US |
| dc.degree.discipline | Animal Science | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Acute kidney injury (AKI) is characterized by a sudden decline in kidney function over a period of days to weeks. Ischemia-reperfusion (IR) is the most common cause of AKI that leads to poor graft function after renal transplantation or after major surgery. Malnutrition is common in AKI patients and is linked to increased mortality. Malnourished AKI patients are at a high risk of developing folate deficiency. However, the molecular mechanisms underlying low folate levels in AKI remain unknown. The general objective of my research was to investigate the mechanism by which renal IR impaired folate status, the effect of 5-methyltetrahydrofolate (5-MTHF) injection against IR-induced oxidative stress caused by renal IR. AKI was induced by surgically clamping the left renal pedicles for 45 min followed by 24 h of reperfusion in rats. Increased plasma creatinine and neutrophil gelatinase-associated lipocalin (NGAL) expression levels indicated that IR caused kidney dysfunction and tubular injury. Circulating folate levels were negatively correlated with creatinine levels. Renal IR decreased the expression of folate receptor 1 (FOLR1) and reduced folate carrier (RFC) in the kidney and proximal tubular cells. Low Sp1/DNA binding activity in the kidneys was linked to decreased FOLR1 expression and plasma folate levels. Injection of (5-MTHF;3 μg/kg BW) in rats improved kidney function, tubular injury and oxidative stress by decreasing lipid peroxidation, restoring kidney glutathione (GSH) levels and enhancing nuclear factor-erythroid factor 2-related factor 2 (Nrf2) antioxidant defense. Renal IR increased lipid peroxidation and decreased GSH levels in the plasma and heart in AKI rats. There was a decrease in cystathionine gamma-lyase (CSE) expression, H2S and nuclear Nrf2 levels in the heart of AKI rats. Taken together, the results of this thesis suggest that 1) renal IR injury can reduce Sp1-mediated folate transporter expression in the kidney resulting in low circulating folate levels, 2) injecting 5-MTHF can attenuate oxidative stress by improving Nrf2 antioxidant defense, and 3) renal IR can induce cardiac oxidative stress by decreasing H2S-mediated cardiac Nrf2 signaling. Improving folate status may be an effective therapeutic option for the prevention and management of AKI. | en_US |
| dc.description.note | May 2023 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/37275 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Acute kidney injury | en_US |
| dc.subject | 5‐methyltetrahydrofolate (5-MTHF) | en_US |
| dc.subject | Oxidative stress | en_US |
| dc.subject | Glutathione | en_US |
| dc.subject | Hydrogen sulfide | en_US |
| dc.subject | Renal ischemia-reperfusion | en_US |
| dc.subject | Distant organ injury | en_US |
| dc.subject | Folic acid | en_US |
| dc.subject | Folate transporters | en_US |
| dc.title | Regulation of folate reabsorption and oxidative stress in acute kidney injury | en_US |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | no | en_US |