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Acute kidney injury induces oxidative stress and distant organ dysfunction due to glutathione depletion
Author(s) -
Shang Yue,
Siow Yaw L.,
Isaak Cara K.,
Karmin O
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.698.4
Subject(s) - glutathione , oxidative stress , kidney , medicine , transsulfuration , ischemia , endocrinology , reperfusion injury , glutathione disulfide , acute kidney injury , renal ischemia , renal function , chemistry , cystathionine beta synthase , pharmacology , biochemistry , cysteine , enzyme
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.