乙酸钠对尿酸性肾病小鼠的降尿酸及肾保护的作用研究

Effects of sodium acetate on lowering uric acid and renal protection in mice with hyperuricemic nephropathy

目的探究乙酸钠(Ace)对尿酸性肾病(HN)小鼠的降尿酸(UA)和肾保护作用及其机制。方法通过腹腔注射氧嗪酸钾联合灌胃腺嘌呤制备尿酸性肾病小鼠模型。小鼠分为空白对照组(0.9%NaCl+0.5%羧甲基纤维素钠)、Ace组(200 mmol·L^(-1)Ace+0.5%羧甲基纤维素钠)、模型组(0.9%NaCl+350 mg·kg^(-1)氧嗪酸钾+70 mg·kg^(-1)腺嘌呤)、实验组(模型组的基础上加用200 mmol·L^(-1)Ace)。观察各组小鼠血清UA和肌酸酐(SCr)水平;用实时荧光定量反转录聚合酶链反应(qRT-PCR)法检测肾损伤分子肾损伤相关标志肾损伤分子-1(Kim-1)和抗衰老基因Klotho,肾纤维化标志Collagen I和Fibronectin,肠道炎症相关因子白细胞介素-1β(IL-1β)、紧密连接蛋白Zo-1 mRNA的表达水平。结果空白对照组、Ace组、模型组和实验组小鼠的血清UA水平分别为(259.52±24.40)、(227.71±35.91)、(604.06±73.55)和(496.24±30.16)μmol·L^(-1),SCr水平分别为(16.85±0.40)、(16.18±0.94)、(22.38±1.56)和(19.78±1.43)μmol·L^(-1),Kim-1 mRNA相对表达水平分别为1.04±0.25、1.17±0.28、13.00±2.87和4.24±3.92,Klotho mRNA相对表达水平分别为1.04±0.15、1.02±0.18、0.43±0.12和0.69±0.12,肾纤维化标志CollagenⅠmRNA相对表达水平分别为1.05±0.15、1.02±0.18、3.19±1.09和1.61±0.55,Fibronectin mRNA相对表达水平分别为1.07±0.18、1.02±0.25、7.86±2.40和3.34±2.10,肠IL-1βmRNA相对表达水平分别为1.00±0.01、1.01±0.03、2.55±0.63和1.21±0.28,肠ZO-1 mRNA相对表达水平分别为1.00±0.07、1.07±0.09、0.54±0.20和0.92±0.17。空白对照组的上述指标与模型组相比,实验组的上述指标与模型组相比,在统计学上差异均有统计学意义(P<0.05,P<0.01,P<0.001)。结论Ace能有效降低HN小鼠的UA水平,显著改善肾损伤和纤维化,其机制可能与改善肠道炎症反应、上调肠道Zo-1/Occuludin通路表达及降低肠道黏膜通透性有关。

Objective To investigate the renal protective effect and mechanism of sodium acetate(Ace)on hyperuricemic nephropathy(HN)in mice.Methods Uric acid nephropathy mice model was prepared by intraperitoneal injection of potassium oxonate combined with adenine gavage.Mice were divided into blank control group(0.9%NaCl+0.5%carboxymethyl cellulose sodium),Ace group(200 mmol·L^(-1) Ace+0.5%carboxymethyl cellulose sodium),model group(0.9%NaCl+350 mg·kg-1 potassium oxonate+70 mg·kg-1 adenine),and experimental group(based on model group with additional 200 mmol·L^(-1) Ace).Serum and urine uric acid(UA)and serum creatinine(SCr)levels were observed in each group.Real-time fluorescence quantitative reverse transcription-polymerase chain reaction(qRT-PCR)was used to detect the expression levels of kidney injury molecule-1(Kim-1)and anti-aging gene Klotho,renal fibrosis markers Collagen Ⅰ and Fibronectin,intestinal inflammation-related factors interleukin-1β(IL-1β),and mRNA expression levels of tight junction proteins Zo-1.Results The serum UA levels of blank control group,Ace group,model group,and experimental group mice were(259.52±24.40),(227.71±35.91),(604.06±73.55),and(496.24±30.16)μmol·L^(-1),respectively;SCr levels were(16.85±0.40),(16.18±0.94),(22.38±1.56),and(19.78±1.43)μmol·L^(-1);Kim-1 mRNA relative expression levels were 1.04±0.25,1.17±0.28,13.00±2.87,and 4.24±3.92;Klotho mRNA relative expression levels were 1.04±0.15,1.02±0.18,0.43±0.12,and 0.69±0.12;CollagenⅠmRNA relative expression levels were 1.05±0.15,1.02±0.18,3.19±1.09,and 1.61±0.55;Fibronectin mRNA relative expression levels were 1.07±0.18,1.02±0.25,7.86±2.40,and 3.34±2.10;intestinal IL-1βmRNA relative expression levels were 1.00±0.01,1.01±0.03,2.55±0.63,and 1.21±0.28;intestinal Zo-1 mRNA relative expression levels were 1.00±0.07,1.07±0.09,0.54±0.20,and 0.92±0.17.The above indicators in blank control group compared with model group,and experimental group compared with model group,all showed statistically significant differences(P<0.05,P<0.01,P<0.001).Conclusion Sodium acetate can effectively reduce UA levels in HN mice,significantly improve renal injury and fibrosis,and its mechanism may be related to the improvement of intestinal inflammatory response and up-regulation of intestinal Zo-1/Occuludin pathway to reduce intestinal mucosal permeability.