Abstract
Chronic kidney disease (CKD) is a worldwide public health problem with an estimated prevalence of 8.2%. This study reports glutathione deficiency, excess oxidative stress, and altered vitamin D metabolism in the kidney of mice fed a high-fat diet (HFD). The levels of GCLC and GCLM gene expression were significantly downregulated and the protein carbonylation level, a hallmark of oxidative damage, was significantly increased in the kidney of HFD-fed mice. While the levels of VD-regulatory genes 1-alpha-hydroxylase (CYP27B1), VDR, and RXRα were significantly downregulated in the kidney of mice fed a HFD, those of 24-hydroxylase (CYP24A1) were significantly elevated. In vitro, GSH deficiency per se causes excess oxidative damage (protein carbonylation), and significantly decreases the levels of VD-regulatory genes (CYP27B1, VDR, and RXRα), but increases levels of CYP24A1 in human renal proximal tubule epithelial cells (RPTEC), similar to findings in the kidney of HFD-fed diabetic mice. L-cysteine supplementation restores GSH and prevents oxidative damage in RPTEC. These studies suggest a potential role of GSH precursor in reducing excess oxidative stress and renal injury that commonly accompanies obesity/diabetes.
Keywords:
CYP24A1; CYP27B1; Glutathione; Human renal proximal tubule epithelial cells; Vitamin D deficiency.
Copyright © 2018. Published by Elsevier Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics*
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25-Hydroxyvitamin D3 1-alpha-Hydroxylase / metabolism
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Animals
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Cysteine / pharmacology
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Diabetes Mellitus, Experimental / enzymology*
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Diabetes Mellitus, Experimental / etiology
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Diabetes Mellitus, Experimental / genetics
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Diabetes Mellitus, Experimental / pathology
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Diet, High-Fat / adverse effects
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Gene Expression Regulation
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Glutamate-Cysteine Ligase / genetics
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Glutamate-Cysteine Ligase / metabolism
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Glutathione / deficiency*
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Humans
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Kidney Tubules, Proximal / metabolism
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Kidney Tubules, Proximal / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Oxidative Stress
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Primary Cell Culture
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Protein Carbonylation
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Receptors, Calcitriol / genetics*
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Receptors, Calcitriol / metabolism
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Renal Insufficiency, Chronic / enzymology*
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Renal Insufficiency, Chronic / etiology
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Renal Insufficiency, Chronic / genetics
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Renal Insufficiency, Chronic / pathology
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Retinoid X Receptor alpha / genetics
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Retinoid X Receptor alpha / metabolism
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Signal Transduction
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Vitamin D3 24-Hydroxylase / genetics*
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Vitamin D3 24-Hydroxylase / metabolism
Substances
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Receptors, Calcitriol
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Retinoid X Receptor alpha
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Vitamin D3 24-Hydroxylase
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25-Hydroxyvitamin D3 1-alpha-Hydroxylase
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GCLM protein, mouse
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Glutamate-Cysteine Ligase
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Glutathione
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Cysteine