PMCID: PMC4385495 DOI: 10.1016/j.prostaglandins.2014.10.006
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.
Prostaglandins & other lipid mediators
Alcohol Dehydrogenase; Animals; Cell Line, Transformed; Cytochrome P-450 CYP2E1; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Ethanol; Hydroxyeicosatetraenoic Acids; Kidney Diseases; Mice; Podocytes; Protein Synthesis Inhibitors; Puromycin
20-Carboxy-arachidonic acid; 20-Hydroxyeicosatetraenoic Acid; Alcohol dehydrogenase; Chronic kidney disease; Ethanol; Glomerular filtration barrier; Oxidative stress; Podocytes; Proteinuria
McCarthy, E. T., Zhou, J., Eckert, R., Genochio, D., Sharma, R., Oni, O., De, A., Srivastava, T., Sharma, R., Savin, V. J., Sharma, M. Ethanol at low concentrations protects glomerular podocytes through alcohol dehydrogenase and 20-HETE. Prostaglandins & other lipid mediators 116-117, 88-98 (2015).