Multiple-Purpose Connectivity Map Analysis Reveals the Benefits of Esculetin to Hyperuricemia and Renal Fibrosis.
Hyperuricemia (HUA) is a risk factor for chronic kidney disease (CKD). Serum uric acid (SUA) levels in CKD stage 3-4 patients closely correlate with hyperuricemic nephropathy (HN) morbidity. New uric acid (UA)-lowering strategies are required to prevent CKD. The multiple-purpose connectivity map (CMAP) was used to discover potential molecules against HUA and renal fibrosis. We used HUA and unilateral ureteral occlusion (UUO) model mice to verify renoprotective effects of molecules and explore related mechanisms. In vitro experiments were performed in HepG2 and NRK-52E cells induced by UA. Esculetin was the top scoring compound and lowered serum uric acid (SUA) levels with dual functions on UA excretion. Esculetin exerted these effects by inhibiting expression and activity of xanthine oxidase (XO) in liver, and modulating UA transporters in kidney. The mechanism by which esculetin suppressed XO was related to inhibiting the nuclear translocation of hexokinase 2 (HK2). Esculetin was anti-fibrotic in HUA and UUO mice through inhibiting TGF-β1-activated profibrotic signals. The renoprotection effects of esculetin in HUA mice were associated with lower SUA, alleviation of oxidative stress, and inhibition of fibrosis. Esculetin is a candidate urate-lowering drug with renoprotective activity and the ability to inhibit XO, promote excretion of UA, protect oxidative stress injury, and reduce renal fibrosis.
['Wang|Yiming|Y|', 'Kong|Weikaixin|W|0000-0002-1070-7136', 'Wang|Liang|L|', 'Zhang|Tianyu|T|', 'Huang|Boyue|B|', 'Meng|Jia|J|', 'Yang|Baoxue|B|0000-0002-7966-2095', 'Xie|Zhengwei|Z|0000-0001-9572-878X', 'Zhou|Hong|H|']
D000818:Animals D002467:Cell Nucleus D004195:Disease Models, Animal D015536:Down-Regulation D005355:Fibrosis D056945:Hep G2 Cells D006801:Humans D033461:Hyperuricemia D007668:Kidney D008297:Male D026901:Membrane Transport Proteins D051379:Mice D008813:Mice, Inbred ICR D019255:NADPH Oxidases D051267:NF-E2-Related Factor 2 D018384:Oxidative Stress D021381:Protein Transport D059467:Transcriptome D014468:Umbelliferones D014517:Ureteral Obstruction D014527:Uric Acid D014969:Xanthine Oxidase
connectivity map esculetin hyperuricemia renal fibrosis hexokinase 2