Abstract: SA-PO611
Role of the Proto-oncogene c-KIT in Tuberous Sclerosis Complex Renal Cystogenesis
Session Information
- Cystic Kidney Diseases: Genetic Causes, Modifiers, and Extrarenal Manifestations
October 26, 2024 | 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: Cystic
Authors
- Barone, Sharon L., University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
- Zahedi, Kamyar A., University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
- Zaidman, Nathan, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
- Brooks, Marybeth, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
- Soleimani, Manoocher, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
Group or Team Name
- Soleimani Lab.
Background
Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2 genes. In the kidney, TSC presents with cysts and angiomyolipomata that can lead to renal failure. The cyst epithelium in TSC mouse models and in TSC patients is comprised of A-intercalated (AIC) cells. Deletion of Foxi1 abrogates the kidney cysts in TSC.
Methods
To identify the molecules critical to kidney cystogenesis in TSC, RNAseq analyses were performed in Tsc1KO (which display many cysts) and Tsc1/Foxi1dKO (that display no cysts) vs. 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, with a profound downregulation in Tsc1/Foxi1dKO mice. Confirmatory analyses 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 c-Kit gene in Tsc1KO mice by generating Tsc1/c-Kit dKO mice completely abrogated kidney cysts and inhibited mTORC1 activity. Expression of c-Kit in M1 CCD cells increased their 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 point to a novel pathway that disrupts the regulation of mTORC1 function and leads to unregulated cell growth and cystogenesis in TSC. The effect of c-Kit ablation in Tsc1KO mice strongly suggest that the modulation of KIT signaling may be a novel treatment for TSC renal cysts.
Funding
- NIDDK Support