Abstract: FR-PO0690
Unique Apical Localization of AQP6 on Cyst Epithelium May Point to Its Role in Fluid Secretion into the Cyst Lumen in Tuberous Sclerosis Complex
Session Information
- Cystic Kidney Diseases: Basic and Translational Research
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Barone, Sharon L., The University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
- Zahedi, Kamyar A., The University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
- Brooks, Marybeth, The University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
- Soleimani, Manoocher, The University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
Background
The expansion of renal cysts in the Tuberous Sclerosis Complex (TSC) depends on the movement of solutes and water into the cyst lumen. The renal cystic epithelium in TSC is primarily composed of hyperproliferating A-intercalated cells (A-ICs). Unlike kidney principal cells lining the cystic epithelium in Polycystic Kidney Disease (Pkd1) mutant mice, the A-ICs do not have a well-documented apical Cl- secreting transporter facilitating fluid secretion into the cyst lumen in TSC. We previously demonstrated enhanced expression of the electrogenic Cl-/H+ exchanger (CLC5), along with its apical localization in renal cyst epithelium in mouse models and individuals with TSC.
Methods
Our RNAseq studies indicate that the mRNA expression of aquaporin 6 (Aqp6), a resident molecule in A-ICs and an intracellular water channel with the ability to transport several anions, including chloride, is significantly enhanced in the kidneys of Tsc1KO, as well as in Tsc2+/- mice.
Results
Northern blot analyses confirmed the enhanced expression of Aqp6 in the kidneys of TSC mouse models. RNA in situ hybridization (ISH) indicated very intense and specific labeling in kidney cyst epithelium. Immunofluorescence microscopy studies demonstrated the distinct localization of AQP6 to the apical domain of epithelial cells lining the renal cysts where they co-localize with H+-ATPase. This is in distinct contrast with wild-type (Wt) mice, where AQP6 is detected in intracellular membrane vesicles in A-ICs. In addition to AQP6 and ClC-5, RAB11A, a small molecule GTPase which plays a critical role in recycling endosomes and the trafficking of H+-ATPase and other molecules to the plasma membrane was detected in the apical membrane of kidney cyst epithelial cells in TSC.
Conclusion
We propose that inhibiting AQP6 and ClC-5 or interfering with their targeting to the apical membrane in cystic epithelia via inhibition of RAB11A could significantly reduce fluid secretion into the cyst lumen and cyst expansion.
Funding
- Veterans Affairs Support