State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, China.
State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, China.
Pharmacol Res. 2024 Nov;209:107407. doi: 10.1016/j.phrs.2024.107407. Epub 2024 Sep 11.
Renal fibrosis (RF) is a common endpoint of various chronic kidney diseases, leading to functional impairment and ultimately progressing to end-stage renal failure. Glycolytic reprogramming plays a critical role in the pathogenesis of fibrosis, which maybe a potential therapeutic target for treating renal fibrosis. Here, we revealed the novel role of ZEB1 in renal fibrosis, and whether targeting ZEB1 is the underlying mechanism for the anti-fibrotic effects of ethyl caffeate (EC) to regulate the glycolytic process. Treatment of EC attenuated the renal fibrosis and inhibited ZEB1 expression in vivo and in vitro, reducing the upregulated expression of glycolytic enzymes (HK2, PKM2, PFKP) and key metabolites (lactic acid, pyruvate). ZEB1 overexpression promoted the renal fibrosis and glycolysis, whereas knockout of ZEB1 apparently attenuated renal fibrosis in vivo and in vitro. EC interacted with ZEB1 to modulate the glycolytic enzymes for suppressing the elevated glycolytic reprogramming during renal fibrosis. In summary, our study reveals that ZEB1 plays an important role in regulating glycolytic reprogramming during the renal tubular epithelial cell fibrosis, suggesting inhibition of ZEB1 may be a potential strategy for treating renal fibrosis. Additionally, EC is a potential new drug candidate for the treatment of renal fibrosis and CKD.
肾纤维化（RF）是各种慢性肾脏病的共同终点，导致功能损害，最终进展为终末期肾衰竭。糖酵解重编程在纤维化的发病机制中起着关键作用，这可能是治疗肾纤维化的潜在治疗靶点。在这里，我们揭示了 ZEB1 在肾纤维化中的新作用，以及靶向 ZEB1 是否是乙基咖啡酸（EC）抗纤维化作用的潜在机制，以调节糖酵解过程。EC 的治疗减轻了体内和体外的肾纤维化，并抑制了 ZEB1 的表达，降低了糖酵解酶（HK2、PKM2、PFKP）和关键代谢物（乳酸、丙酮酸）的上调表达。ZEB1 的过表达促进了肾纤维化和糖酵解，而 ZEB1 的敲除明显减轻了体内和体外的肾纤维化。EC 与 ZEB1 相互作用，调节糖酵解酶，抑制肾纤维化过程中升高的糖酵解重编程。总之，我们的研究表明，ZEB1 在调节肾小管上皮细胞纤维化过程中的糖酵解重编程中起着重要作用，提示抑制 ZEB1 可能是治疗肾纤维化的一种潜在策略。此外，EC 可能是治疗肾纤维化和 CKD 的一种潜在新药候选物。
