摘 要：为探索高尿酸血症诱导的肾纤维化大鼠肾组织中锌α2糖蛋白（ZAG）与细胞外信号调节激酶1/2（ERK1/2）和p38丝裂原活化蛋白激酶（p38 MAPK）形成反馈通路调控肾上皮间质转化（EMT）的机制，将64只SPF级雄性Wistar大鼠分为正常组和高尿酸组，再对每组的一半大鼠进行过表达ZAG处理，观察大鼠肾组织中ZAG的表达水平与ERK1/2和p38 MAPK信号通路的交互作用。结果发现：相较于正常组，高尿酸组大鼠肾组织中EMT相关分子的mRNA及蛋白质的表达显著上调；在高尿酸组中，过表达ZAG降低了高尿酸血症肾病大鼠的血清尿酸（SUA）水平，缓解了大鼠的肾功能障碍，延缓了大鼠的肾纤维化进展，同时过表达ZAG显著降低了高尿酸血症肾病大鼠肾组织中丝裂原活化蛋白激酶（MAPK）通路中相关蛋白及其mRNA的表达。结果表明，过表达ZAG可以抑制ERK1/2和p38 MAPK信号通路的激活并延缓EMT的进程，以缓解高尿酸血症导致的肾脏损伤和肾纤维化，从而减轻大鼠的高尿酸血症肾病。这些发现为ZAG潜在的高尿酸血症肾病预防作用开辟了新的研究途径。
关键词：锌α2糖蛋白；p38丝裂原活化蛋白激酶；细胞外信号调节激酶1/2；肾纤维化；上皮间质转化；高尿酸血症肾病
中图分类号：R361               文献标志码：A                    DOI：10.3969/j.issn.1007-7146.2025.04.008

Abstract: To explore the mechanism by which zinc-α2-glycoprotein (ZAG) forms a feedback loop with extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) to regulate renal epithelial-mesenchymal transition (EMT) in renal tissue of hyperuricemia-induced renal fibrosis rats, 64 SPF-grade male Wistar rats were divided into a normal group and a hyperuricemia group. Half of the rats in each group were subjected to ZAG overexpression treatment to observe the interaction between ZAG expression levels and ERK1/2 and p38 MAPK signaling pathways in renal tissue. The results showed that compared with the normal group, the mRNA and protein levels of EMT-related molecules in the renal tissue of the hyperuricemia group were significantly upregulated. In the hyperuricemia group, ZAG overexpression reduced the serum uric acid (SUA) level, alleviated renal dysfunction, and delayed the progression of renal fibrosis in hyperuricemic nephropathy rats. Meanwhile, ZAG overexpression significantly decreased the expression of related proteins and their mRNA in the mitogen-activated protein kinase (MAPK) pathway in the renal tissue of hyperuricemic nephropathy rats. The findings indicate that ZAG overexpression inhibits the activation of ERK1/2 and p38 MAPK signaling pathways and delays the process of EMT, thereby alleviating renal injury and fibrosis caused by hyperuricemia and reducing hyperuricemic nephropathy in rats. These results open up a new research prospect for the potential preventive effect of ZAG on hyperuricemic nephropathy.
Key words: ZAG; p38 MAPK; ERK1/2; renal fibrosis; epithelial-mesenchymal transition; hyperuricemic nephropathy
（Acta Laser Biology Sinica, 2025, 34(4): 354-364）