Abstract: SA-PO0109
Primary Cilia and the Exocyst Regulate Urinary Extracellular Vesicle Signaling and Renal Tubule Cell Injury Response
Session Information
- ADPKD and Cystic Kidney Disease - 3
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Gerges, Marie, Medical University of South Carolina, Charleston, South Carolina, United States
- Zuo, Xiaofeng, Medical University of South Carolina, Charleston, South Carolina, United States
- Lipschutz, Joshua H., Medical University of South Carolina, Charleston, South Carolina, United States
Background
Urinary extracellular vesicles (uEVs) are emerging as important mediators of cell-cell communication, termed “urocrine signaling.” We previously showed that the exocyst, a highly conserved trafficking complex required for ciliogenesis, regulates EV production and cargo composition. We further showed that exocyst dysfunction alters MAPK/ERK signaling, epithelial cell repair, and mitochondrial homeostasis. Here, we investigated whether EVs derived from cells and mice with varying levels of Exoc5, an essential exocyst component, transmit signaling phenotypes to recipient cells.
Methods
EVs were isolated by serial ultracentrifugation from the media of Madin-Darby canine kidney (MDCK), Exoc5-knockdown MDCK (Exoc5-KD), and Exoc5 ciliary-targeting-sequence mutant MDCK (Exoc5-CTS-mut) cells, as well as from the urine of proximal tubule-specific Exoc5 knockout (Exoc5 KO) and polycystic kidney disease 1 (PKD1) RC/RC mice. Confocal microscopy demonstrated efficient uptake of fluorescently labeled EVs by recipient MDCK cells. EV-mediated signaling was assessed by ERK phosphorylation in recipient MDCK and murine inner medullary collecting duct 3 (mIMCD3) cells and by recovery of transepithelial electrical resistance (TEER) following oxidative injury.
Results
EVs from Exoc5-CTS-mut and Exoc5-KD cells increased ERK phosphorylation in MDCK cells compared to EVs from control MDCK cells. uEVs isolated from Exoc5 KO mice induced greater ERK phosphorylation in recipient mIMCD3 cells than uEVs from wild-type mice. Similarly, uEVs from PKD1 RC/RC mice induced greater ERK phosphorylation than uEVs from wild-type mice. EVs from Exoc5-KD and Exoc5-CTS-mut cells led to impaired TEER recovery following injury with hydrogen peroxide, indicating defective repair.
Conclusion
These findings support a model in which primary cilia and the exocyst regulate uEV signaling. EVs derived from cilia-deficient or cystic renal epithelia transmit pathogenic signals, including enhanced ERK phosphorylation and defective repair. This is important as other groups have shown that inhibiting ERK phosphorylation reduced cystogenesis in the pcy and inv mouse models of PKD. These data provide functional evidence supporting urocrine signaling in kidney disease and suggest that disease-associated uEVs may participate in the spread of pathogenic signaling within the nephron.
Funding
- Veterans Affairs Support