Fujimoto Daisuke, Umemoto Shuro, Mizumoto Teruhiko, Kanki Tomoko, Hata Yusuke, Nishiguchi Yoshihiko, Date Ryosuke, Zhang Jingxuan, Kakizoe Yutaka, Izumi Yuichiro, Adachi Masataka, Kojima Hirotatsu, Yokoi Hideki, Mukoyama Masashi, Kuwabara Takashige
Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
Drug Discovery Initiative, The University of Tokyo, Tokyo, Japan.
Sci Rep. 2025 Apr 25;15(1):14436. doi: 10.1038/s41598-025-98894-0.
Extracellular vesicles (EVs) are important mediators of intercellular communication and play key roles in the regulation of pathophysiological processes. In diabetic kidney disease (DKD), it has been reported that macrophages recruited in the mesangial region may play pathogenic roles through inducing local inflammation in glomeruli. We focused on EV-mediated crosstalk between mesangial cells (MC) and macrophages as a novel therapeutic target for DKD. EVs released from MC induced inflammation in macrophages and the effect was enhanced under high-glucose conditions. For discovering novel therapeutic agents which can inhibit such EV-mediated mechanisms, drug repositioning is considered as an effective tool. We established a unique screening strategy and screened agents to aim at maximizing their specificity and potency to inhibit EV mechanisms, along with minimizing their toxicity. We succeeded in identifying alvespimycin, an HSP90 inhibitor. Treatment of diabetic rats with alvespimycin significantly suppressed mesangial expansion, inflammatory gene activation including macrophage markers, and proteinuria. The inhibitory effect on EV uptake was specific to alvespimycin compared with other known HSP90 inhibitors. MC-derived EVs are crucial for inflammation by intercellular crosstalk between MC and macrophages in DKD, and alvespimycin effectively ameliorated the progression of DKD by suppressing EV-mediated actions, suggesting that EV-targeted agents can be a novel therapeutic strategy.
细胞外囊泡（EVs）是细胞间通讯的重要介质，在病理生理过程的调节中发挥关键作用。在糖尿病肾病（DKD）中，据报道，系膜区募集的巨噬细胞可能通过诱导肾小球局部炎症发挥致病作用。我们将重点放在EV介导的系膜细胞（MC）与巨噬细胞之间的相互作用上，将其作为DKD的一种新型治疗靶点。MC释放的EVs可诱导巨噬细胞发生炎症，且在高糖条件下这种作用会增强。为了发现能够抑制这种EV介导机制的新型治疗药物，药物重新定位被认为是一种有效的工具。我们建立了一种独特的筛选策略，并筛选药物，旨在最大限度地提高其抑制EV机制的特异性和效力，同时将其毒性降至最低。我们成功鉴定出一种HSP90抑制剂——阿维西霉素。用阿维西霉素治疗糖尿病大鼠可显著抑制系膜扩张、包括巨噬细胞标志物在内的炎症基因激活以及蛋白尿。与其他已知的HSP90抑制剂相比，阿维西霉素对EV摄取的抑制作用具有特异性。在DKD中，MC来源的EVs通过MC与巨噬细胞之间的细胞间相互作用对炎症至关重要，而阿维西霉素通过抑制EV介导的作用有效改善了DKD的进展，这表明以EV为靶点的药物可能是一种新型治疗策略。
