Abstract
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.
Highlights
Hyperuricemia (HUA) is associated with gout, obesity, hypertension, atherosclerosis, the metabolic syndrome, lipid disorders, cardiovascular disease, and chronic kidney disease (CKD) [1,2]
We found that uric acid (UA) exposure moderately increased intracellular ROS production which decreased in response to esculetin treatment (Figure 5A)
Esculetin treatment abolished the translocation of hexokinase 2 (HK2) to the nucleus whilst the nuclear import of Nrf2 was upregulated in UA-treated HepG2 cells (Figure 5F). These results suggest that esculetin decreases the expression of xanthine oxidase (XO) through inhibiting the nuclear translocation of HK2 in UA-induced HEPG2
Summary
Hyperuricemia (HUA) is associated with gout, obesity, hypertension, atherosclerosis, the metabolic syndrome, lipid disorders, cardiovascular disease, and CKD [1,2]. HUA is an independent risk factor for cardiovascular disease and hypertension, which further contributes to the development and progression of CKD [5]. The effective management of HUA is important to delay the development and progression of CKD and reduce cardiovascular complications in hyperuricemic patients. According to the specific conditions of the patients, treatments with a low impact on renal function should be used to monitor adverse reactions [13,14] This highlights the need for anti-hyperuricemic agents with greater effectiveness and fewer side effects. Multiple gene expression profiles with a common phenotype, obesity, have been combined for CMAP analysis [15]. We propose that applications of CMAP using multiple-purpose strategies to target both HUA and renal fibrosis can aid the discovery of novel and more effective compounds targeting a single phenotype. We verified the beneficial effects of esculetin on HUA with HN and renal fibrosis, which were consistent with CMAP results, and revealed pathways targeted
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