Resveratrol, a novel inhibitor of GLUT9, ameliorates liver and kidney injuries in a d-galactose-induced ageing mouse model via the regulation of uric acid metabolism
Resveratrol, a novel inhibitor of GLUT9, ameliorates liver and kidney injuries in a d-galactose-induced ageing mouse model via the regulation of uric acid metabolism
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DOI：
10.1039/d1fo00538c
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发表时间：
2021-05-31
期刊：
影响因子：
6.1
通讯作者：
Pang, Jianxin
中科院分区：
文献类型：
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作者：
Li, Lu;Li, Yongmei;Pang, Jianxin
越来越多的证据表明，长期注射d-半乳糖（d-gal）可以模拟自然衰老，并导致肝和肾损伤。先前的研究表明，d-gal增加小鼠的尿酸（UA）水平。尿酸水平的增加引起炎症，加速氧化应激，加重肝和肾损伤。氧化应激和炎症在衰老过程中起着至关重要的作用。因此，降低衰老小鼠的UA水平可改善肝脏和肾脏损伤。葡萄糖转运蛋白9（GLUT 9）负责体内UA的重吸收，其抑制有助于下调UA水平。本研究采用我们实验室建立的膜片钳技术，在体外研究了GLUT 9抑制剂白藜芦醇（RSV）的降尿酸活性。这项研究是第一项证明RSV在体外通过GLUT 9有效抑制UA摄取的研究（IC 50 = 68.77 μ M）。还进行了体内研究以研究RSV对d-gal诱导的肝和肾损伤的可能保护作用。RSV通过下调GLUT 9 mRNA和蛋白表达显著降低血清UA水平，并促进多余UA通过尿液排泄。生化分析表明，RSV显著下调了长期d-gal处理引起的血清丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、血尿素氮（BUN）和肌酐（CRE）水平异常升高，有效改善了肝、肾组织病理损伤，提高了超氧化物歧化酶（SOD）活性，降低了丙二醛（MDA）含量。RSV还下调了衰老小鼠肝脏和肾脏中炎性细胞因子、白细胞介素IL-6、IL-1 β和肿瘤坏死因子（TNF）-α的表达。我们的研究结果为衰老诱导的肝脏和肾脏损伤的治疗策略提供了新的见解，并揭示了RSV诱导衰老个体UA水平降低的新机制。
Accumulating evidence has shown that chronic injection of d-galactose (d-gal) can mimic natural ageing and induce liver and kidney injury. Previous studies showed that d-gal increased uric acid (UA) levels in mice. The increase in UA levels caused inflammation, accelerated oxidative stress, and aggravated liver and kidney injury. Oxidative stress and inflammation play vital roles in the ageing process. Therefore, reducing the levels of UA in ageing mice improved liver and kidney injury. Glucose transporter 9 (GLUT9) is responsible for the reabsorption of UA in the body, and its inhibition helps downregulate UA levels. The present study investigated the UA-lowering activity of the GLUT9 inhibitor resveratrol (RSV) using the patch clamping technique established in our laboratory in vitro. This research is the first study to demonstrate that RSV effectively inhibits UA uptake via GLUT9 (IC50 = 68.77 mu M) in vitro. An in vivo study was also performed to investigate the possible protective effect of RSV on d-gal-induced liver and kidney injury. RSV significantly reduced serum UA levels via the downregulation of GLUT9 mRNA and protein expression and promoted the excretion of excess UA through urine. Biochemical analysis showed that RSV significantly downregulated abnormal increases in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine (CRE) caused by long-term d-gal treatment, which effectively improved pathological damage, increased superoxide dismutase (SOD) activity and decreased the content of malondialdehyde (MDA) in the liver and kidneys. RSV also downregulated the expression of the inflammatory cytokines, interleukin IL-6, IL-1 beta and tumor necrosis factor (TNF)-alpha in the liver and kidneys of ageing mice. Our findings provide new insights into the treatment strategies for ageing-induced liver and kidney injury and reveal a new mechanism of RSV-induced reduction in UA levels in ageing individuals.