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Abstract: TH-PO883

Exosome-Mediated Tubulointerstitial Communication Promotes Renal Fibrosis in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Wen, Jin, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
  • Livingston, Man J., Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Zhang, Wei, Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Guo, Chunyuan, Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Yuan, Yanggang, Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Fu, Ping, West China Hospital of Sichuan University, Chengdu, SiChuan, China
  • Dong, Zheng, Augusta University Medical College of Georgia, Augusta, Georgia, United States
Background

Renal tubular injury initiates fibroblast activation and drives overproduction of extracellular matrix, leading to renal fibrosis which is a final common pathway in progressive kidney diseases including diabetic kidney disease(DKD). However, it is unclear how injured tubular epithelial cells relay signals to neighboring fibroblasts and trigger the differentiation of fibroblasts to myofibroblasts. Recently, exosomes have been recognized as crucial mediators of intercellular communication. We hypothesized that exosomes might be involved in the communication between injured tubular cells and fibroblasts during the progress of DKD.

Methods

Exosomes were isolated from kidney tissues and mouse proximal tubular cells by differential centrifugation. In in vivo, renal cortex of Akita mice and STZ-induced C57/b6 mice were examined. In in vitro, BUMPT cells were cultured with normal glucose(NG) or high glucose(HG) for 8 days to collect exosomes in the conditioned medium(CM). Exosomes were characterized by TEM, NTA and western blot. The content of exosomes was analyzed by proteomics. To study the effect of tubular cell exosomes on fibroblasts, the tubular CM-derived exosomes were added to NRK-49 fibroblasts for 48 hrs, followed by the evaluation of cell proliferation and fibrosis.

Results

Exosome secretion decreased in renal cortex of DKD mice as compared to non-diabetic mice. Consistently, HG-incubated BUMPT cells had lower exosomes than NG cells. Notably, the exosomes from HG-incubated BUMPT cells stimulated higher levels of proliferation, morphologic change, and production of fibronectin, a-SMA, and collagen I in fibroblasts. 15 proteins showed differential expression in the exosomes from HG BUMPT-cells versus those from NG cells. Cytoscape analysis suggested two correlation networks of the differentially expressed genes. The higher expression of Eno1 and close relationship with clinical manifestation in DKD were further proved using Nephroseq v5 online platform.

Conclusion

DKD is associated with a decreased ability of exosome production and/or secretion in renal tubular cells. The exosomes from HG-incubated tubular cells are more effective in stimulating the proliferation and activation of fibroblasts. Thus, exosomes may provide a mechanism of tubulointerstitial communication in renal fibrosis and disease progression in DKD.