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Abstract: TH-PO210

Role of Exosome-Mediated Intraglomerular Cross-Talk Between Mesangial Cells and Macrophages in the Progression of Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Fujimoto, Daisuke, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto City, Kumamoto Prefecture, Japan
  • Umemoto, Shuro, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto City, Kumamoto Prefecture, Japan
  • Kuwabara, Takashige, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto City, Kumamoto Prefecture, Japan
  • Date, Ryosuke, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto City, Kumamoto Prefecture, Japan
  • Hata, Yusuke, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto City, Kumamoto Prefecture, Japan
  • Mizumoto, Teruhiko, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto City, Kumamoto Prefecture, Japan
  • Izumi, Yuichiro, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto City, Kumamoto Prefecture, Japan
  • Mukoyama, Masashi, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto City, Kumamoto Prefecture, Japan
Background

Extracellular vesicles (EVs) are important mediators of intercellular communication in the regulation of physiological and pathophysiological processes. Particularly, exosome-mediated intercellular crosstalk has been addressed in several disorders such as cancer and lifestyle-related diseases. In diabetic kidney disease (DKD), it has been reported that macrophages infiltrating the mesangial region may play an important role through inducing local inflammation in glomeruli. However, mechanisms for DKD progression and roles of exosome-mediated processes remain elusive.

Methods

We focused on exosomes as possible key factors acting in a paracrine manner in glomeruli and examined the effects of mesangial cell (MC)-derived exosomes on macrophages in culture. In order to identify new therapeutic agents, we screened a validated compound library that can efficiently inhibit this mechanism and also studied their effects on DKD.

Results

Exosomes derived from MCs induced inflammation in macrophages, demonstrated by the NFkB transcriptional activity, and TNFα and IL-1β expressions. The effect was significantly enhanced in exosomes from MCs cultured under high-glucose conditions compared to low-glucose conditions. We observed that fluorescent-labeled exosomes were endocytosed by macrophages in vitro and in vivo. Next, we conducted drug screening using a compound library to find candidates that could specifically and effectively inhibit the inflammation process induced by exosomes. The screening was divided into four steps, and we succeeded in narrowing down the list to 30 candidate compounds from a total of 1,364 compounds. Finally, an HSP90 inhibitor, alvespimycin, was identified as a compound with strong inhibitory effects on both exosome uptake and the NFkB transcriptional activity. Treatment of a diabetic rat model with alvespimycin significantly reduced proteinuria and tended to suppress mesangial expansion.

Conclusion

Local inflammation by exosome-mediated crosstalk between MCs and macrophages could be involved in DKD progression. Furthermore, alvespimycin, one of the HSP90 inhibitors obtained by drug screening, can effectively ameliorate this process, suggesting that such mechanism could become a novel therapeutic strategy for DKD.