Center of Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, China.
Am J Physiol Renal Physiol. 2010 Aug;299(2):F336-46. doi: 10.1152/ajprenal.00053.2010. Epub 2010 May 19.
Urate is produced as the major end product of purine metabolism. In the last decade, the incidence of hyperuricemia increased markedly, and similar trends in the epidemiology of metabolic syndrome have been observed. Hyperuricemia is associated with renal disease, and recent studies have reported that mild hyperuricemia results in hypertension, intrarenal vascular disease, and renal injury. This has led to the hypothesis that uric acid may contribute to renal fibrosis and progressive renal disease. Our purpose was to investigate the relationship between uric acid and renal tubular injury. We applied the method of intraperitoneal injection of uric acid to generate the hyperuricemic mouse model. Compared with the saline injection group, the expression of lysyl oxidase (LOX) and fibronectin in kidneys was increased significantly in hyperuricemic groups. In vitro, uric acid significantly induced NRK-52E cells to express the ECM marker fibronectin, as well as LOX, which plays a pivotal role in ECM maturation, in a time- and dose-dependent manner. Upregulation of the urate transporter URAT1, which is located in the apical membrane of proximal tubules, sensitized the uric acid-induced fibronectin and LOX induction, while both knocking down URAT1 expression in tubular epithelial cells by RNA interference and inhibiting URAT1 function pharmacologically attenuated LOX and fibronectin expression. Furthermore, knockdown of LOX expression by a small interfering RNA strategy led to a decrease in fibronectin abundance induced by uric acid treatment. In addition, evidence of a uric acid-induced activation of the NF-kappaB signaling cascade was observed. Our findings highlight a need for carefully reevaluating our previous view on the pathological roles of hyperuricemia in the kidney and nephropathy induced by uric acid in clinical practice.
尿酸是嘌呤代谢的主要终产物。在过去的十年中，高尿酸血症的发病率显著增加，代谢综合征的流行病学也呈现出类似的趋势。高尿酸血症与肾脏疾病有关，最近的研究报告称，轻度高尿酸血症可导致高血压、肾内血管疾病和肾损伤。这导致了尿酸可能导致肾纤维化和进行性肾病的假说。我们的目的是研究尿酸与肾小管损伤之间的关系。我们采用腹腔注射尿酸的方法构建高尿酸血症小鼠模型。与生理盐水注射组相比，高尿酸血症组肾脏中赖氨酰氧化酶（LOX）和纤维连接蛋白的表达明显增加。在体外，尿酸显著诱导 NRK-52E 细胞表达 ECM 标志物纤维连接蛋白和 LOX，LOX 在 ECM 成熟中起关键作用，呈时间和剂量依赖性。尿酸转运体 URAT1 的上调，位于近端肾小管的顶膜，使尿酸诱导的纤维连接蛋白和 LOX 诱导作用敏感，而通过 RNA 干扰在肾小管上皮细胞中敲低 URAT1 表达和药理学抑制 URAT1 功能均可减弱 LOX 和纤维连接蛋白的表达。此外，通过小干扰 RNA 策略敲低 LOX 表达可减少尿酸处理诱导的纤维连接蛋白丰度。此外，还观察到尿酸诱导 NF-κB 信号级联激活的证据。我们的研究结果强调，需要重新评估我们以前对高尿酸血症在肾脏中的病理作用以及尿酸引起的肾病的看法，这在临床实践中非常重要。
