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Decreased secretion and profibrotic activity of tubular exosomes in diabetic kidney disease.

Tubular changes contribute to the development of renal pathologies in DKD, including interstitial fibrosis. It is unclear how tubular cells relay signals to interstitial fibroblasts. Recently, exosomes have been recognized as crucial mediators of intercellular communication. We hypothesized that exosomes secreted from tubular cells may stimulate fibroblasts for interstitial fibrosis in DKD. In this study, we isolated exosomes from the renal cortex of DKD mice and high glucose treated mouse proximal tubular cells. Compared to non-diabetic mice, exosome secretion in kidney tissues decreased in DKD mice. Likewise, high glucose incubation reduced exosome secretion in mouse kidney proximal tubular BUMPT cells. To study the effect of tubular cell exosomes on fibroblasts, the exosomes from BUMPT cells were added to renal fibroblast NRK-49F cell cultures. Notably, the exosomes from high glucose conditioned BUMPT cells (HG-Exo) induced higher proliferation, significant morphologic change, and substantial production of fibronectin, a-SMA and collagen I in fibroblasts. Proteomics analysis was further performed to profile the proteins within tubular cell exosomes. Interestingly, twenty-two proteins were found differentially expressed between HG-Exo and NG-Exo. Cytoscape analysis suggested two PPI networks in these exosomal differentially expressed proteins (DEPs). Gene expression analysis via Nephroseq showed a correlation of Eno1 expression with DKD clinical manifestation. In conclusion, DKD is associated with a decrease in exosome secretion in renal tubular cells. The exosomes from high glucose conditioned tubular cells may regulate the proliferation and activation of fibroblasts, contributing to the paracrine signaling mechanism responsible for the pathological onset of renal interstitial fibrosis in DKD.