Abstract: FR-PO0688
Critical Role of the Proto-Oncogene c-KIT in Tuberous Sclerosis Complex (TSC)-Associated Kidney Cystogenesis
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
- 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
- Zhang, Wenzheng, Albany Medical College Department of Regenerative and Cancer Cell Biology, Albany, New York, United States
- Zaidman, Nathan, The University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
- Soleimani, Manoocher, New Mexico VA Health Care System, Albuquerque, New Mexico, United States
Background
Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2 genes. In the kidney, TSC presents with cysts and angiomyolipomas that can lead to renal failure. The cyst epithelium in TSC mouse models and in individuals with TSC is primarily comprised of A-intercalated (AIC) cells. Deletion of the transcription factor, Foxi1, which is a master regulator of intercalated cell development and growth, abrogates the kidney cysts in TSC.
Methods
To identify the molecules critical to kidney cystogenesis in TSC, RNAseq analyses were performed in the kidneys of Tsc1KO (which display many cysts) and compared to Tsc1/Foxi1dKO (that display no cysts) vs. wildtype (WT) mice. The mRNA and protein expression of differentially expressed transcripts (DET) was confirmed, their localization was ascertained and the effect of their ablation on cystogenesis was determined.
Results
RNAseq identified c-Kit as a vigorously up-regulated DET in the kidneys of Tsc1KO mice, along with a profound downregulation in Tsc1/Foxi1dKO mice. Confirmatory studies proved robust expression of c-Kit in the kidneys of Tsc1KO mice, and immunofluorescence microscopy showed its localization to the basolateral membrane of cyst epithelia. Ablation of the c-Kit gene in Tsc1KO mice by generating Tsc1/c-Kit dKO mice completely abrogated kidney cysts and inhibited mTORC1 activity. Treatment with imatinib, a c-KIT inhibitor, significantly prevented cyst formation in the kidneys of Tsc1KO mice. Additional studies showed that transfection with Foxi1 in M-1 cortical collecting duct (CCD) cells significantly induced c-Kit expression. Follow-up studies in M-1 CCD cells transfected with c-Kit increased cell proliferation, along with the activation of ERK1/2 and RSK1 signaling. The potentiation of ERK1/2 and RSK1 signaling were also demonstrated in kidneys of Tsc1KO mice and inhibited in Tsc1/c-KIT dKO mice.
Conclusion
Activation of c-KIT, a proto-oncogene and a resident molecule in AIC cells in Tsc1KO mice, points to a novel pathway leading to unregulated cell growth and cystogenesis in TSC, consequent to robust mTORC1 activation. The effect of c-Kit ablation or treatment with a c-KIT inhibitor (imatinib) on kidney cystogenesis in Tsc1KO mice strongly suggests that the modulation of KIT signaling may be a novel treatment for TSC renal cysts.
Funding
- NIDDK Support