Kidney Week

Abstract: SA-OR25

Intercalated Cells and the Transcription Factor FOXI1 Drive the Kidney Cystogenesis in Tuberous Sclerosis Complex

Session Information

• Kidneyomics: From Cysts to Populations
  October 24, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Barone, Sharon L., University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States

Sharon L. Barone, MS

• Zahedi, Kamyar A., University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States

Kamyar A. Zahedi,

• Brooks, Marybeth, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States

Marybeth Brooks,

• Henske, Elizabeth P., Brigham and Women's Hospital, Boston, Massachusetts, United States

Elizabeth P. Henske,

• Bissler, John J., LeBonheur Center for Children in Crisis, Memphis, Tennessee, United States

John J. Bissler,

• Yu, Jane J., University of Cincinnati College of Medicine, Cincinnati, Ohio, United States

Jane J. Yu,

• Soleimani, Manoocher, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States

Manoocher Soleimani,

Background

Tuberous sclerosis complex (TSC) is caused by mutations in either the TSC1 or TSC2 gene and affects multiple organs, including the kidney. Patients can present with benign tumors (angiomyolipomata) and cysts, which can lead to kidney failure. Factors that promote cyst formation and tumor growth in TSC are poorly understood.

Methods

Mice with principal cell specific inactivation of Tsc1 were generated. In addition, mice with double deletion of Foxi1 and Tsc1 (Foxi1/Tsc1 double KO) or carbonic anhydrase 2 (CAII) and Tsc1 (CAII/Tsc1 double KO) were generated based on RNA-seq and expression studies.

Results

Tsc1 KO mice showed numerous kidney cortical cysts, which were overwhelmingly comprised of A-intercalated (A-IC) cells that showed strong expression of apical V H⁺-ATPase. RNA-seq studies demonstrated a 3-fold enhanced expression of Foxi1, which is critical to the development of IC cells and regulation of V H⁺-ATPase and CAII. The expression of Foxi1 in Pkd1 mice remained unchanged vs. WT mice. Deleting Foxi1 completely abrogated the cyst burden in Foxi1/Tsc1 dKO mice (Kidney MRI in image 1) and caused a profound reduction in V H⁺-ATPase expression in the A-IC cells. Mice with double deletion of Tsc1 and CAII, a regulator of V H⁺-ATPase, showed significant reductions in cyst burden and increased longevity vs. Tsc1 KO mice.

Conclusion

We propose that A-IC cells, V H⁺-ATPase and CAII are critical to cystogenesis, and their inhibition or inactivation is associated with a significant protection against cyst generation and/or enlargement in TSC. Carbonic anhydrase inhibitors may be viable treatments for the prevention of kidney cyst expansion in TSC. Supplementing carbonic anhydrase inhibitors with HCO₃^- (to minimize the untoward side effects of metabolic acidosis) may be warranted.

MRI examination of kidneys of Tsc1 and Foxi1/Tsc1 double Ko mice

Funding

• Veterans Affairs Support