Abstract: FR-PO0074
It Takes More Than Two: MUC1-C, a New Candidate Promoting Kidney Cystogenesis in Tuberous Sclerosis Complex (TSC)
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
- Soleimani, Manoocher, New Mexico VA Health Care System, Albuquerque, New Mexico, United States
- Al-bataineh, Mohammad, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Brooks, Marybeth, New Mexico VA Health Care System, Albuquerque, New Mexico, United States
- Ford, Aisha, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Powers, Nasja, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- 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
Background
The epithelium of renal cysts in TSC is primarily composed of proliferating A-intercalated cells (A-ICs). The exact molecular machinery mediating kidney cystogenesis in TSC remains speculative.
Investigating molecular and biochemical adaptations in pre-cystic and cystic kidneys from TSC mouse models will yield distinct insights that can be leveraged to develop novel treatments.
Methods
RNA-seq and expression studies were used to identify and localize differentially expressed transcripts in the kidney cystic epithelium of TSC mouse models.
Results
RNA-seq studies identified the proto-oncogene Muc1 (mucin 1) as a highly expressed mRNA in the kidneys of TSC mouse models. Immunofluorescence labeling demonstrated: 1) co-localization of MUC1 and H+-ATPase in the apical and subapical regions of kidney cystic epithelial cells in mouse and human with TSC; and 2) robust expression of both MUC1 and PCNA in proliferating A-IC cells lining the kidney cysts.
Western blotting and confocal microscopy demonstrated that MUC1 is cleaved, yielding a truncated c-terminus, MUC1-C, which is translocated into the nuclei of cells lining the cysts.
Stable Muc1 transfection in cultured MDCK cells enhances cell proliferation. MUC1-C is known to increase cell proliferation in various epithelial tumors by repressing the Hippo pathway; thereby, allowing the transcription co-activators, YAP and TAZ, to translocate to the nucleus and drive cell growth. Our Western blots demonstrate robust upregulation of YAP and TAZ levels and their nuclear translocation, along with MUC1-C, in Tsc1 KO mouse kidney cells. Further studies indicate robust upregulation of hypoxia-inducible factor 1α (HIF1α) in the nuclear fraction of cystic epithelial cells in these kidneys.
Studies in Muc1 KO, WT, and Muc1-overexpressing transgenic mice (Muc1tg) indicate that the levels of MUC1-C are significantly enhanced in the kidneys of Muc1tg compared to WT and Muc1 KO mice and are associated with the downregulation of AMPK activity, pointing to the critical role of MUC1-C overexpression in the potentiation of mTORC1 and increased cell proliferation in TSC kidney cyst epithelium.
Conclusion
Identification of MUC1-C and its interacting partners, YAP, TAZ, and HIF1a, provides crucial insights into mechanisms of tubular cell proliferation and renal cystogenesis in TSC.
Funding
- NIDDK Support