Abstract: FR-PO0073
Arginine Vasopressin Receptor 1A (AVPR1A) in Tuberous Sclerosis Complex (TSC) Kidney Cystogenesis and Its Potential as a Therapeutic Target
Session Information
- ADPKD and Cystic Kidney Disease - 2
October 23, 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
- Zahedi, Kamyar A., New Mexico VA Health Care System, Albuquerque, New Mexico, United States
- Barone, Sharon L., New Mexico VA Health Care System, Albuquerque, New Mexico, United States
- Brooks, Marybeth, New Mexico VA Health Care System, Albuquerque, New Mexico, United States
- Zaidman, Nathan, The University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
- In, Julie Goeun, The University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
- Soleimani, Manoocher, New Mexico VA Health Care System, Albuquerque, New Mexico, United States
Background
In the kidney, TSC presents with cysts and angiomyolipomata. Using a model of TSC renal disease caused by the ablation of the Tsc1 gene in principal cells (Tsc1KO), it was shown that renal cystogenesis is driven by the expansion of actively proliferating A-intercalated (A-IC) cells that express both Tsc1 and Tsc2. The molecules and mechanisms underlying the expansion of A-IC cells and TSC renal cysts are not completely elucidated. Deletion of Foxi1 in the kidneys of Tsc1 KO mice (Tsc1/Foxi1 dKO) abrogated kidney cysts.
Methods
Comparison of RNA seq in Tsc1KO, Tsc1/Foxi1dKO, and WT mice identified several robustly expressed genes in the kidneys of Tsc1KO vs. WT mice that were suppressed in Tsc1/Foxi1dKO mice. The mRNA and protein expression of differentially expressed genes, and their localization, were assessed by fluorescence in situ hybridization (FISH), Western blotting, and immunohistochemistry and immunofluorescence microscopy. Stable transfectants were generated to assess their effects on cell proliferation.
Results
The expression of mRNA for A-IC cell-specific Avpr1a was significantly elevated in the cyst-bearing kidneys of Tsc1KO mice. In comparison, the Avpr1a transcripts were. suppressed in the cyst-free kidneys of Tsc1/Foxi1dKO mice. Localization of Avpr1a mRNA revealed that it is primarily expressed in the epithelium of TSC renal cysts. Additional microscopic studies revealed that AVPR1A is localized to the basolateral membrane and cytoplasmic compartment of cystic epithelial cells. In vitro studies demonstrated Foxi1 transfection of M-1 cells enhanced AVPR1A expression. Additionally, AVPR1A overexpression increased proliferation of M-1 cells. Treatment of Tsc1KO mice with relcovaptan, an AVPR1A-specific inhibitor, reduced mTORC1 activation and renal cyst burden.
Conclusion
In TSC renal cystogenesis, AVPR1A is expressed on the basolateral membrane of the A-IC cells in renal cystic epithelium and plays a critical role in cell proliferation and cystogenesis.
Funding
- Other NIH Support