title: Ethanol at low concentrations protects glomerular podocytes through alcohol dehydrogenase and 20-HETE.
abstract: Clinical studies suggest cardiovascular and renal benefits of ingesting small amounts of ethanol. Effects of ethanol, role of alcohol dehydrogenase (ADH) or of 20-hydroxyeicosatetraenoic acid (20-HETE) in podocytes of the glomerular filtration barrier have not been reported. We found that mouse podocytes at baseline generate 20-HETE and express ADH but not CYP2e1. Ethanol at high concentrations altered the actin cytoskeleton, induced CYP2e1, increased superoxide production and inhibited ADH gene expression. Ethanol at low concentrations upregulated the expression of ADH and CYP4a12a. 20-HETE, an arachidonic acid metabolite generated by CYP4a12a, blocked the ethanol-induced cytoskeletal derangement and superoxide generation. Ethanol at high concentration or ADH inhibitor increased glomerular albumin permeability in vitro. 20-HETE and its metabolite produced by ADH activity, 20-carboxy-arachidonic acid, protected the glomerular permeability barrier against an ADH inhibitor, puromycin or FSGS permeability factor. We conclude that ADH activity is required for glomerular function, 20-HETE is a physiological substrate of ADH in podocytes and that podocytes are useful biosensors to understand glomeruloprotective effects of ethanol.
authors.affiliation: Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States.
authors.forename: Ellen T
authors.initials: ET
authors.lastname: McCarthy
authors.affiliation: Research Service, Kansas City VA Medical Center, Kansas City, MO, United States.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Research Service, Kansas City VA Medical Center, Kansas City, MO, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Eckert
authors.affiliation: Research Service, Kansas City VA Medical Center, Kansas City, MO, United States.
authors.forename: David
authors.initials: D
authors.lastname: Genochio
authors.affiliation: Research Service, Kansas City VA Medical Center, Kansas City, MO, United States.
authors.forename: Rishi
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Research Service, Kansas City VA Medical Center, Kansas City, MO, United States.
authors.forename: Olurinde
authors.initials: O
authors.lastname: Oni
authors.affiliation: Research Service, Kansas City VA Medical Center, Kansas City, MO, United States.
authors.forename: Alok
authors.initials: A
authors.lastname: De
authors.affiliation: Research Service, Kansas City VA Medical Center, Kansas City, MO, United States; Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, United States.
authors.forename: Tarak
authors.initials: T
authors.lastname: Srivastava
authors.affiliation: Research Service, Kansas City VA Medical Center, Kansas City, MO, United States.
authors.forename: Ram
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States; Research Service, Kansas City VA Medical Center, Kansas City, MO, United States.
authors.forename: Virginia J
authors.initials: VJ
authors.lastname: Savin
authors.affiliation: Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States; Research Service, Kansas City VA Medical Center, Kansas City, MO, United States. Electronic address: Mukut.sharma@va.gov.
authors.forename: Mukut
authors.initials: M
authors.lastname: Sharma
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D000818:Animals; D002461:Cell Line, Transformed; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D000431:Ethanol / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D011691:Puromycin / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D011500:Protein Synthesis Inhibitors; D000431:Ethanol; D011691:Puromycin; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; C493210:Cyp4a12a protein, mouse; D000072470:Cytochrome P450 Family 4
keywords: 20-Carboxy-arachidonic acid; 20-Hydroxyeicosatetraenoic Acid; Alcohol dehydrogenase; Chronic kidney disease; Ethanol; Glomerular filtration barrier; Oxidative stress; Podocytes; Proteinuria