Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China; Hebei University of Traditional Chinese Medicine, No.326, Xinshi South Road, Qiaoxi District, Shijiazhuang 05000, China.
Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China; Acupuncture and moxibustion and Massage College of Hebei University of Chinese Medicine, No.3 Xingyuan Road, Luquan District, Shijiazhuang 050200, China.
Biomed Pharmacother. 2024 Nov;180:117589. doi: 10.1016/j.biopha.2024.117589. Epub 2024 Oct 16.
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.
肾间质纤维化（RIF）是糖尿病肾病（DKD）的一种重要病理变化，可由内皮-间充质转化（EndMT）引起。淋巴管生成，由血管内皮生长因子-C（VEGF-C）/血管内皮生长因子受体-3（VEGFR-3）通路介导，在 DKD 相关 RIF 的发展中起着关键作用。尽管许多研究表明恩格列净在治疗肾损伤方面的疗效，但它对 DKD 相关 RIF 中的淋巴管生成及其潜在机制的影响尚不清楚。在本研究中，评估了 DKD 患者肾间质中的显著淋巴管生成。随后，我们在小鼠模型、高糖（HG）刺激的肾 HK-2 细胞系和人淋巴管内皮细胞（hLEC）中探讨了 DKD 相关 RIF 与淋巴管生成之间的关系，并评估了恩格列净对这些过程的影响。结果表明，HG 诱导淋巴管生成，通过促进炎症反应加重 RIF。此外，hLEC 通过 EndMT 直接促进 DKD 相关 RIF 的进展。进一步分析表明，肾小管上皮细胞（TEC）是 VEGF-C 的效应细胞，TEC 的上皮-间充质转化（EMT）与淋巴管的 EndMT 同时发生。恩格列净通过抑制 VEGF-C/VEGFR3 通路和减少淋巴管生成来抑制 DKD 中的 RIF。总之，本研究阐明了 DKD 中淋巴管生成、EndMT 和 RIF 之间的相互作用，并为恩格列净治疗 DKD 的机制提供了新的见解。
