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Kidney Week

Abstract: FR-PO978

Proliferation of Intercalated Cells in Cystic Epithelium of Principal Cell-Specific Tsc1-KO Mice

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: 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
  • Somlo, Stefan, Yale University , New Haven, Connecticut, United States
  • Xu, Jie, University of Cincinnati, Cincinnati, Ohio, United States
  • Bissler, John J., Le Bonheur Children's Hospital and St. Jude Children's Research Hospital, Memphis, Tennessee, United States
  • Soleimani, Manoocher, University of Cincinnati, Cincinnati, Ohio, United States

Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivation of either TSC1 or TSC2 genes and affects multiple organs. In the kidney, TSC presents with development of angiomyolipomas and renal cysts, which lead to renal failure. Despite our knowledge regarding its genetics, little is known about the promotion of cyst growth and enlargement in TSC.


Mice with principal cell specific inactivation of Tsc1 (Tsc1 floxed mice crossed with Aqp-2-promoter driven cre mice) develop an increasing number of cortical cysts as they age.


Single and double immunofluorescence labeling studies demonstrated that cyst epithelium is predominantly comprised of A-intercalated (IC) cells, as shown by strong expression of apical H+-ATPase and pro-renin receptor (PRR). Cyst formation in Tsc1-KO mice is preceded by extensive areas of proliferation in the cortical collecting ducts (CCD), which are exclusively comprised of mitotically active (PCNA-positive) A-intercalated cells. This is distinct from a mouse model of ADPKD (Pkd1-KO mice), in which CCD-derived cystic epithelium contains numerous principal cells. Expression of Foxi1 transcription factor, a master regulator of intercalated cells and their acid base transport machinery, robustly increased in kidneys of young Tsc1-KO mice. Kidney cysts show mTORC1 activation in intercalated cells as determined by phosphorylation of p70-S6 kinase 1 (S6K1). Kidney cysts from humans with TSC display a similar preponderance of intercalated cells in their epithelium.


We propose that the robust proliferation and propagation of A-intercalated cells is crucial to kidney cystogenesis in Tsc1-KO mice. We further propose that unlike cysts in PKD, which respond to AVP antagonism by reduction in their fluid secretion and size, TSC1 cysts, which hardly contain any principal cells will be resistant to AVP antagonists. We suggest that the pathogenesis of kidney cyst formation and fluid secretion into the cyst in TSC is distinct from PKD, is associated with proliferation of intercalated cells and gradual disappearance of principal cells in cyst epithelium, is independent of AVP-receptor/ADH axis and is energized by H+-ATPase and Pro-renin Receptor.


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