Pterostilbene and allopurinol reduce fructose-induced podocyte oxidative stress and inflammation via microRNA-377.
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.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China.
Wei
W
Wang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China.
Xiao-Qin
XQ
Ding
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China.
Ting-Ting
TT
Gu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China.
Lin
L
Song
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China.
Jian-Mei
JM
Li
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China.
Qiao-Chu
QC
Xue
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China. Electronic address: kongld@nju.edu.cn.
Ling-Dong
LD
Kong
D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016166:Free Radical Scavengers / Q000494:pharmacology; D005632:Fructose / Q000633:toxicity*; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects*; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D035721:Pterocarpus / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D013549:Sweetening Agents / Q000633:toxicity
D000975:Antioxidants; D002352:Carrier Proteins; D016166:Free Radical Scavengers; D053583:Interleukin-1beta; C000598764:MIRN377 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013267:Stilbenes; D013549:Sweetening Agents; C486715:TXNIP protein, human; C107773:pterostilbene; D005632:Fructose; D000493:Allopurinol; D006861:Hydrogen Peroxide; D020170:Caspase 1
Allopurinol; Free radicals; Fructose; MiR-377; NLRP3 inflammasome; Oxidative stress; Podocyte injury; Pterostilbene; TXNIP