Pterostilbene and allopurinol reduce fructose-induced podocyte oxidative stress and inflammation via microRNA-377.

Abstract

High dietary fructose is an important causative factor in the development of metabolic syndrome-associated glomerular podocyte oxidative stress and injury. Here, we identified microRNA-377 (miR-377) as a biomarker of oxidative stress in renal cortex of fructose-fed rats, which correlated with podocyte injury and albuminuria in metabolic syndrome. Fructose feeding increased miR-377 expression, decreased superoxide dismutase (SOD) expression and activity, and caused O2(-) and H2O2 overproduction in kidney cortex or glomeruli of rats. This reactive oxygen species induction increased p38 MAPK phosphorylation and thioredoxin-interacting protein (TXNIP) expression and activated the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome to produce interleukin-1β in kidney glomeruli of fructose-fed rats. These pathological processes were further evaluated in cultured differentiated podocytes exposed to 5mM fructose, or transfected with miR-377 mimic/inhibitor and TXNIP siRNA, or co-incubated with p38 MAPK inhibitor, demonstrating that miR-377 overexpression activates the O2(-)/p38 MAPK/TXNIP/NLRP3 inflammasome pathway to promote oxidative stress and inflammation in fructose-induced podocyte injury. Antioxidants pterostilbene and allopurinol were found to ameliorate fructose-induced hyperuricemia, podocyte injury, and albuminuria in rats. More importantly, pterostilbene and allopurinol inhibited podocyte miR-377 overexpression to increase SOD1 and SOD2 levels and suppress the O2(-)/p38 MAPK/TXNIP/NLRP3 inflammasome pathway activation in vivo and in vitro, consistent with the reduction of oxidative stress and inflammation. These findings suggest that miR-377 plays an important role in glomerular podocyte oxidative stress, inflammation, and injury driven by high fructose. Inhibition of miR-377 by antioxidants may be a promising therapeutic strategy for the prevention of metabolic syndrome-associated glomerular podocyte injury.

• Authors: Wei Wang, Xiao-Qin Ding, Ting-Ting Gu, Lin Song, Jian-Mei Li, Qiao-Chu Xue, Ling-Dong Kong
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 83 Pg. 214-26 (Jun 2015) ISSN: 1873-4596 [Electronic] United States
• PMID: 25746774 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Carrier Proteins
• Free Radical Scavengers
• Interleukin-1beta
• MIRN377 microRNA, rat
• MicroRNAs
• RNA, Messenger
• Reactive Oxygen Species
• Stilbenes
• Sweetening Agents
• TXNIP protein, human
• pterostilbene
• Fructose
• Allopurinol
• Hydrogen Peroxide
• Caspase 1

Topics

• Allopurinol (pharmacology)
• Animals
• Antioxidants (metabolism)
• Blotting, Western
• Carrier Proteins (genetics, metabolism)
• Caspase 1 (genetics, metabolism)
• Cells, Cultured
• Free Radical Scavengers (pharmacology)
• Fructose (toxicity)
• Gene Expression Regulation
• Hydrogen Peroxide (metabolism)
• Immunoenzyme Techniques
• Inflammation (chemically induced, drug therapy, genetics, pathology)
• Interleukin-1beta (genetics, metabolism)
• Kidney Glomerulus (drug effects, metabolism, pathology)
• Male
• MicroRNAs (genetics)
• Oxidative Stress (drug effects)
• Podocytes (drug effects, metabolism, pathology)
• Pterocarpus (chemistry)
• RNA, Messenger (genetics)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Stilbenes (pharmacology)
• Sweetening Agents (toxicity)