Renal interstitial fibrosis (RIF) is a significant pathological change in diabetic kidney disease (DKD) that can be induced by endothelial-to-mesenchymal transition (EndMT). Lymphangiogenesis, mediated by the vascular endothelial growth factor-C (VEGF-C)/vascular endothelial growth factor receptor-3 (VEGFR-3) pathway, plays a crucial role in the development of RIF in DKD. Although numerous studies have demonstrated the efficacy of empagliflozin in treating renal injury, its effects on lymphangiogenesis in DKD-related RIF and the underlying mechanisms remain unclear. In the present study, significant lymphangiogenesis was assessed in the renal interstitium of patients with DKD. We subsequently explored the relationship between DKD-related RIF and lymphangiogenesis in mouse models, high-glucose (HG)-stimulated renal HK-2 cell lines, and human lymphatic endothelial cells (hLECs). Additionally, we evaluated the effects of empagliflozin on these processes. The results revealed that HG induces lymphangiogenesis, which exacerbates RIF by promoting inflammatory responses. Furthermore, hLECs directly contributed to the progression of DKD-related RIF through EndMT. Further analysis revealed that tubular epithelial cells (TECs) act as effector cells for VEGF-C, with the epithelial-to-mesenchymal transition (EMT) of TECs occurring concurrently with the EndMT of lymphatic vessels. Empagliflozin inhibited RIF in DKD by suppressing the VEGF-C/VEGFR3 pathway and reducing lymphangiogenesis. In conclusion, this study elucidates the interplay between lymphangiogenesis, EndMT, and RIF in DKD and provides new insights into the mechanism by which empagliflozin treats DKD.Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.