title: Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury.
abstract: Ischemia-reperfusion is a common cause for acute kidney injury and can lead to distant organ dysfunction. Glutathione is a major endogenous antioxidant and its depletion directly correlates to ischemia-reperfusion injury. The liver has high capacity for producing glutathione and is a key organ in modulating local and systemic redox balance. In the present study, we investigated the mechanism by which kidney ischemia-reperfusion led to glutathione depletion and oxidative stress. The left kidney of Sprague-Dawley rats was subjected to 45 min ischemia followed by 6 h reperfusion. Ischemia-reperfusion impaired kidney and liver function. This was accompanied by a decrease in glutathione levels in the liver and plasma and increased hepatic lipid peroxidation and plasma homocysteine levels. Ischemia-reperfusion caused a significant decrease in mRNA and protein levels of hepatic glutamate-cysteine ligase mediated through the inhibition of transcription factor Nrf2. Ischemia-reperfusion inhibited hepatic expression of cystathionineγ-lyase, an enzyme responsible for producing cysteine (an essential precursor for glutathione synthesis) through the transsulfuration pathway. These results suggest that inhibition of glutamate-cysteine ligase expression and downregulation of the transsulfuration pathway lead to reduced hepatic glutathione biosynthesis and elevation of plasma homocysteine levels, which, in turn, may contribute to oxidative stress and distant organ injury during renal ischemia-reperfusion.
authors.affiliation: St. Boniface Hospital Research Centre, Winnipeg, MB, Canada; Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Yue
authors.identifier: 0000-0002-8576-4338
authors.initials: Y
authors.lastname: Shang
authors.affiliation: St. Boniface Hospital Research Centre, Winnipeg, MB, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada; Agriculture and Agri-Food Canada, Winnipeg, MB, Canada.
authors.forename: Yaw L
authors.initials: YL
authors.lastname: Siow
authors.affiliation: St. Boniface Hospital Research Centre, Winnipeg, MB, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Cara K
authors.initials: CK
authors.lastname: Isaak
authors.affiliation: St. Boniface Hospital Research Centre, Winnipeg, MB, Canada; Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Karmin
authors.identifier: 0000-0002-2163-9458
authors.initials: K
authors.lastname: O
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015536:Down-Regulation; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000032:analysis / Q000096:biosynthesis*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008107:Liver Diseases / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051267:NF-E2-Related Factor 2; D021122:Protein Subunits; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione