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Kidney Week

Abstract: SA-OR095

Carbonic Anhydrase II (CAII) and Intercalated Cells (ICs) Drive Kidney Cystogenesis in Tuberous Sclerosis Complex (TSC)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Barone, Sharon L., University of Cincinnati, Cincinnati, Ohio, United States
  • Zahedi, Kamyar A., University of Cincinnati, Cincinnati, Ohio, United States
  • Brooks, Marybeth, University of Cincinnati, Cincinnati, Ohio, United States
  • McDonough, Alicia A., Keck School of Medicine of USC, Los Angeles, California, United States
  • Somlo, Stefan, Yale University, New Haven, Connecticut, United States
  • Henske, Elizabeth P., Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Yu, Jane J., University of Cincinnati, Cincinnati, Ohio, United States
  • Soleimani, Manoocher, University of Cincinnati, Cincinnati, Ohio, United States

TSC is caused by mutations in either TSC1 or TSC2 genes and affects multiple organs, including kidney, lung and brain. In the kidney, TSC presents with benign tumors (angiomyolipomas) and cysts, which eventually lead to kidney failure. Little is known about the factors that promote cyst generation and enlargement in tuberous sclerosis.


Principal cell (PC) specific inactivation of Tsc-1 or Tsc-2 was accomplished by crossing mice with either a Tsc-1 or Tsc-2 floxed construct with mice expressing cre recombinase under the control of Aqp-2 promoter.


Tsc-1 KO as well Tsc-2 KO (Physiol. Report 2019) develop numerous cortical cysts, which are overwhelmingly (>95%) comprised of A-ICs, as identified by strong apical expression of V H+-ATPase B subunit and basolateral AE1 (Slc4a1), with remaining cells (<5%) expressing Aqp-2, a marker of PCs. ICs lining the cysts expressed intact Tsc-1 gene and exhibited vigorous proliferation and mTORC1 activation.
RNA-seq and confirmatory northern hybridization and/or immunohistochemical studies demonstrated the robust expression of the transcription factor Foxi1, a master regulator of ICs H+-ATPase, Cl-/HCO3- exchanger AE1 and CAII in cyst epithelia in Tsc-1 KO mice, but not in Pkd1 mutant mice. Given the vital role of CAII in H+-ATPase activity and ICs viability/proliferation, we tested the hypothesis that CAII may play a critical role in the cytogenesis in TSC.


Our studies demonstrate that CAII deletion in Tsc-1 KO mice profoundly inhibited the cyst burden (see image). Compared with Tsc-1 single mutant mice, CAII/Tsc-1 double mutant mice displayed much smaller cysts, with significantly fewer proliferating ICs, and decreased mTORC activity. We propose that the H+-ATPase and CAII are critical to cystogenesis, and their inhibition or inactivation is associated with significant protection against cyst generation/enlargement in TSC.


  • NIDDK Support