Acute kidney injury induces oxidative stress and distant organ dysfunction due to glutathione depletion
Bibliographic record
Abstract
Ischemia‐reperfusion is a common cause for acute kidney injury and often complicated by distant organ dysfunction. Oxidative stress plays an important role in ischemia‐reperfusion induced local and distant organ injury. However, the mechanisms of AKI induced distant organ injury are not well understood. Glutathione is a major endogenous antioxidant and its depletion directly correlates to ischemia‐reperfusion injury. The liver has a high capacity for producing glutathione and is a key organ that regulates local and systemic redox balance. Liver function is often compromised in patients with acute kidney injury. In the present study, we investigated the mechanism by which kidney ischemia‐reperfusion induced oxidative stress and downregulated glutathione biosynthesis in the liver. The left kidney of Sprague‐Dawley rats was subjected to 45min ischemia followed by 6h reperfusion. Renal ischemia‐reperfusion impaired kidney and liver function as indicated by increased plasma creatinine, aspartate aminotransferase and alanine aminotransferase levels. This was accompanied by a significant reduction in glutathione levels in the liver and plasma. There was a marked elevation of hepatic lipid peroxidation and plasma homocysteine levels. Renal ischemia‐reperfusion caused a significant decrease in mRNA and protein levels of glutamate‐cysteine ligase (catalytic and modifier subunits) which regulated the rate‐limiting reaction in glutathione biosynthesis. A decrease in gene expression of glutamate‐cysteine ligase subunits was mediated through inhibition of a transcription factor Nrf‐2. Renal ischemia‐reperfusion also inhibited hepatic expression of cystathionine‐gamma‐lyase (CSE), an enzyme responsible for producing cysteine (an essential precursor for glutathione synthesis) through the transsulfuration pathway. In conclusion, our study has identified that decreased expression of glutamate‐cysteine ligase, a key enzyme for glutathione biosynthesis as well as reduced CSE‐mediated cysteine production through the transsulfuration pathway may be responsible for hepatic glutathione depletion upon renal IR. This, in turn, dampens the antioxidant defense mechanism and contributes to renal ischemia‐reperfusion induced oxidative stress. Support or Funding Information This study was supported, in part, by NSERC and St. Boniface Hospital Research Centre.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".