The aim of this paper is to explore the mechanism of zinc-u2-glycoprotein (ZAG) forming a feedback pathway with extracellular signal- regulated kinase 1/2 (ERK1/2) and p38 to regulate epithelial mesenchymal transition (EMT) in rat re- nal epithelial cells (NRK-52E) induced by high uric acid environment, we divided NRK-52E into normal control group and high uric acid-induced group which was stimulated by 20 mg/dL uric acid for 48 h, and the cells in each group were transfected with overexpression ofZAG and knocked down respectively, to observe the interactions between ZAG expression level and ERK1/2 and p38 signaling pathways in the cells. The results revealed that the mRNA and protein expression of EMT-related molecules were elevated in rat kidney cells under high uric acid environment compared with the normal culture group (P <0.05); up-reg- ulation of ZAG decreased the expression of mitogen-activated protein kinase kinase (MAPKK), ERK1/2, p38, activated tran- scription factor-2 (ATF2) and protein kinase B (PKB or Akt) mRNA in this pathway in rat kidney epithelial cells under high uric acid environment culture (P <0.01), while the downregulation ofZAG increased (P <0.05). At the protein level, the expression of MAPKK, p38 and Akt decreased in the ZAG up-regulated group compared to the untransfected group (P <0.05, P <0.01, P <0.001); and the expression of ERK1/2, p38 and Akt was elevated in the ZAG down-regulated group (P <0.001, P <0.05, P <0.01). The results suggest that transfection up-regulation of ZAG decreases the expression of laminin and vimentin mRNA, the marker genes related to EMT in NRK-52E; regulation of ZAG expression in NRK-52E can play a positive role in ERK1/2 and p38 signaling pathways, and thus inhibit renal cell EMT. This study provides an experimental basis for clinical treatment of hyperuricemic nephropathy (HN).