Identification and verification of novel therapeutic agents for diabetic kidney disease based on exosome-targeted high-throughput chemical screening

Abstract Exosomes 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 exosome-mediated crosstalk between mesangial cells (MC) and macrophages as a novel therapeutic target for DKD. Exosomes 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 exosome-mediated mechanisms, drug repositioning is considered as aneffective tool. We established a unique screening strategy and screened agents to aim at maximizing their specificity and potency to inhibit exosomal 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 exosome uptake was specific to alvespimycin compared with other known HSP90 inhibitors. MC-derived exosomes are crucial for inflammation by intercellular crosstalk between MC and macrophages in DKD, and alvespimycin effectively ameliorated the progression of DKD by suppressing exosome-mediated actions, suggesting that exosome-targeted agents can be a novel therapeutic strategy.