Cytochrome P450-2E1 is involved in aging-related kidney damage in mice through increased nitroxidative stress

Abstract

The aim of this study was to investigate the role of cytochrome P450-2E1 (CYP2E1) in aging-dependent kidney damage since it is poorly understood. Young (7 weeks) and aged female (16–17 months old) wild-type (WT) and Cyp2e1-null mice were used. Kidney histology showed that aged WT mice exhibited typical signs of kidney aging such as cell vacuolation, inflammatory cell infiltration, cellular apoptosis, glomerulonephropathy, and fibrosis, along with significantly elevated levels of renal TNF-α and serum creatinine than all other groups. Furthermore, the highest levels of renal hydrogen peroxide, protein carbonylation and nitration were observed in aged WT mice. These increases in the aged WT mice were accompanied by increased levels of iNOS and mitochondrial nitroxidative stress through altered amounts and activities of the mitochondrial complex proteins and significantly reduced levels of the antioxidant glutathione (GSH). In contrast, the aged Cyp2e1-null mice exhibited significantly higher antioxidant capacity with elevated heme oxygenase-1 and catalase activities compared to all other groups, while maintaining normal GSH levels with significantly less mitochondrial nitroxidative stress compared to the aged WT mice. Thus, CYP2E1 is important in causing aging-related kidney damage most likely through increasing nitroxidative stress and that CYP2E1 could be a potential target in preventing aging-related kidney diseases.

Pomegranate prevents binge alcohol-induced gut leakiness and hepatic inflammation by suppressing oxidative and nitrative stress

“…One of the main causes of alcohol-induced organ damage is the elevated oxidative and nitrative (nitroxidative) stress through activating pro-oxidant enzymes/genes while suppressing the antioxidant levels including glutathione [39] , [40] . Some of the pro-oxidant enzymes induced or activated after alcohol exposure are CYP2E1 and iNOS, which are responsible for production of reactive oxygen and nitrogen species, respectively, contributing to elevated nitroxidative stress [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] . In fact, alcohol-induced CYP2E1 protein expression has been directly linked to the development of both steatosis and inflammation [2] , [9] , [15] .…”

“…Indeed, the specific involvement of CYP2E1 in ALD has been demonstrated by utilizing CYP2E1 overexpressed transgenic (Tg), knock-out (KO), and knock-in (KI) mice [2] , [12] , [13] . Recently, our group reported that CYP2E1 is also involved in n-6 fatty acid containing western-style high-fat diet induced non-alcoholic steatohepatitis [14] and aging-related liver and kidney damage [15] , [16] through increasing the oxidative and nitrative (nitroxidative) stress. Furthermore, both intestinal and hepatic CYP2E1 induced (i.e., via protein stabilization) by chronic alcohol drinking [17] or binge alcohol exposure seems critically important in promoting alcohol-mediated increased nitroxidative stress, gut leakage, and endotoxemia, contributing to apoptosis of hepatocytes and steatohepatitis [18] , [19] .…”

The p53/p21/p16 and PI3K/Akt signaling pathways are involved in the ameliorative effects of maltol on D‐galactose‐induced liver and kidney aging and injury

“…The cytochrome P450 enzyme system, mainly CYP2E1, is involved in the metabolism of endogenous and exogenous substances (Shirato, Homma, Lee, Kurahashi, & Fujii, 2017; Ye et al, 2012). Even though there was no additional increase in the CYP2E1 levels in aged WT mice, the increased levels of oxidative stress in WT mice could have been produced through CYP2E1‐mediated metabolism of endogenous substrates throughout the life span (Abdelmegeed, Choi, Ha, & Song, 2017). CYP2E1 is an effective generator of ROS, so the accumulation of this enzyme may represent a pathophysiological condition.…”

3-D Human Renal Tubular Organoids Generated from Urine-Derived Stem Cells for Nephrotoxicity Screening

“…The cytochrome P450-2E1 (CYP2E1) is an enzyme that is constitutively expressed in hepatic and extrahepatic tissues, including the kidney. 46 As a common target for exogenous agent detoxification, 47 CYP2E1 is an effective generator of reactive oxygen species and produces powerful oxidants ( i.e ., hydroxyl radical) in the presence of catalytic iron to induce cell injury. 46 , 48 …”