Abstract: FR-PO342
Tubule-Derived Extracellular Vesicles Promotes Fibroblast Activation in Kidney Fibrosis
Session Information
- Mechanisms Associated with Kidney Fibrosis - I
November 03, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Chronic Kidney Disease (Non-Dialysis)
- 308 CKD: Mechanisms of Tubulointerstitial Fibrosis
Authors
- Liu, Xi, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Zhou, Lili, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Liu, Youhua, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background
Kidney fibrogenesis is a complex process involving frequent cell-cell communication. Extracellular vesicles (EVs), consisting of exosomes and microvesicles, are increasingly recognized as an essential vehicle mediating cell-cell communication in both physiologic and pathologic conditions. Because tubular epithelium is the major constitute of kidney parenchyma and the epicenter of kidney injury, we hypothesized that tubular cells, in response to injury, may increase their production and release of EVs containing proteins, mRNAs and microRNAs, which act on interstitial fibroblasts, leading to their activation. In this study, we tested this hypothesis by in vitro and in vivo approaches.
Results
In human kidney proximal tubular cells (HKC-8), TGF-β1 induced marked increase in the release of EVs. Conditioned media collected after TGF-β1 treatment promoted rat kidney interstitial fibroblast (NRK-49F) activation, proliferation and matrix production, compared with controls. However, depletion of EVs from TGF-β1-treated HKC-8 cell conditioned media abolished its action on NRK-49F cells, suggesting a predominant role of the EVs in mediating tubule-fibroblast communication. Interestingly, we found that Shh signal components were markedly induced in the EVs released by TGF-β1-treated HKC-8 cells. Knockdown of Shh in HKC-8 cells by RNAi abolished the tubular EVs-mediated induction of Gli1, Snail1, α-SMA, fibronectin, and collagen I in NRK-49F cells. In mouse model of kidney fibrosis induced by UUO, the secretion of EVs was dramatically increased, and blockade of EVs secretion with small molecule inhibitor DMA suppressed myofibroblast activation, inhibited fibronectin and collagen I expression and ameliorated renal fibrotic lesions.
Conclusion
These results indicate that tubule-derived EVs play a critical role in initiating fibroblast activation and development of renal fibrotic lesions. Our data also suggest that Shh signal components in the EVs may be responsible, at least partially, for mediating the tubule-fibroblast communication in renal fibrogenesis.
Funding
- Government Support - Non-U.S.