Abstract: FR-PO0689
Kidney Cyst Epithelia in Tuberous Sclerosis Complex Exhibit Expansion of A-Intercalated but Loss of B-Intercalated and Principal Cells: Role of FOXI1, FOXP1, and DMRT2 Transcription Factors
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
- Soleimani, Manoocher, New Mexico VA Health Care System, Albuquerque, New Mexico, United States
- Zahedi, Kamyar A., New Mexico VA Health Care System, Albuquerque, New Mexico, United States
- Brooks, Marybeth, 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
Background
The kidney cystic epithelium in Tuberous Sclerosis Complex (TSC) is primarily comprised of A-intercalated cells (A-ICs). This unique cell phenotype is distinct from kidney cysts in Autosomal Dominant Polycystic Kidney Disease (ADPKD) and is observed in the kidneys of TSC patients and in mouse TSC models. The dominance of A-ICs lining the kidney cysts is independent of the status of TSC in the principal cells (PC), as this phenotype is also detected in the kidney cysts in Tsc2+/- and pericyte specific Tsc1KO mice.
Methods
These studies explore the mechanism of TSC kidney cystogenesis using 1) principal cell-specific Tsc1KO mice, 2) Tsc1/Car2dKO mice, 3) Tsc2+/- mice, 4) Tsc1/Foxi1dKO, and 5) Foxi1KO mice. They examine the molecular basis of the expansion of A-ICs, the loss of B-intercalated cells (B-ICs), the status of Tsc1 and Tsc2 molecules in A-ICs lining the cysts, and the trans-differentiation of principal cells to intercalated cells in cyst epithelia.
Results
RNA transcriptome and immunofluorescence/immunohistochemical analyses comparing kidneys of 47 days old principal cell-specific Tsc1KO (with many large cysts) vs. aged-matched Tsc1/Car2dKO mice (with few small cysts), 105 days Tsc1/Car2dKO mice (with numerous large cysts), Tsc1/Foxi1 dKO (no cysts), Foxi1KO, and wild type (WT) mice demonstrate the following in TSC mouse models: 1) Increased expression of transcription factors FOXI1 and FOXP1 and their downstream target DMRT2, with the consequent dominance of A-ICs in cyst epithelia; 2) A significant reduction in Hmx2 transcription factor with the resultant loss of B-ICs in cyst epithelia; and 3) Detection of intact TSC1 and TSC2 in A-ICs in cyst epithelial cells.
Conclusion
In conclusion, kidney TSC cysts reveal enhanced expression of FOXI1 and FOXP1 and their target DMRT2 that is associated with hyperproliferation of A-ICs with intact TSC1/2, and the downregulation of Hmx2, and the consequent loss of B-ICs. These results indicate that TSC-mediated kidney cytogenesis is driven by changes that promote the expansion of A-IC and reductions in B-IC and PC numbers.
Funding
- Veterans Affairs Support