Unraveling Signaling Mechanisms of Renal Extracellular Vesicles in Ciliopathies
Background
Extracellular vesicles (EVs) play a crucial role in kidney development and disease by influencing key signaling pathways. Recent research shows that the primary cilium, a microtubule-based signaling organelle, coordinates the release and composition of renal small EVs (smEVs), affecting their signaling molecule content. Changes in EV-mediated signaling due to ciliary dysfunction could thus impact tissue homeostasis leading to renal malformation and other pathologies.
Methods
In our study, we focused on the functional significance of ciliary smEVs to unravel the mechanistic defects underlying cell communication in ciliopathic kidney dysfunction. Using renal cell lines from both mouse models and ciliopathy patients we isolated ciliary associated EVs and examined their content and bioactivity.
Results
We observed distinct differences between ciliary mutant smEVs compared to control. Specifically, we found an enrichment of proteins involved in multiple signaling pathways associated with renal homeostasis, such as WNT signaling and proteasomal degradation. Regarding their bioactivity, we demonstrated that enrichment of proteasomal proteins in the ciliary mutant smEVs leads to enhanced proteasomal activity. Furthermore, we showed that these smEVs cells exert a WNT-attenuating effect on recipient cells, which appears to be predominantly attributable to their protein content. We further evaluated their functionality, with particular emphasis on their impact on metabolic changes in target cells and effect on renal tube polarisation.
Conclusion
These findings underscore the potential of smEVs in modulating key cellular processes through their bioactive protein content. Thus, providing insights into the communication pathways of renal cells via ciliary EVs and shedding light on in processes underlying renal ciliopathies.
Keywords
Cilia, Renal Ciliopathies, Bioactivity, WNT, EVs
Funding/Acknowledgments
This work was supported by the Johannes Gutenberg University Mainz Stufe1 Funding program.
Authors
Alina Frei1, Sara Mesic-Sivic1, Ann-Kathrin Volz1, Karsten Boldt2, Eva-Maria Krämer-Albers3, and Helen May-Simera1 (Corresponding Author: may-simera[at]uni-mainz[dot]de)