# The Role of Intercalated Cells and Their Acid Base and Electrolyte Transport Machinery in Kidney Cystogenesis by Tuberous Sclerosis

> **NIH VA I01** · ALBUQUERQUE VA MEDICAL CENTER · 2024 · —

## Abstract

Abstract. Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder, which is caused
by inactivating mutations in either the TSC1 or TSC2 gene and affects multiple organs, including kidney
and lung. The disease affects over two million people worldwide, with a large proportion developing
angiomyolipomata and cysts, which eventually lead to renal failure. While the initial genetic events of TSC
have been delineated, little is known about the biological processes and factors that facilitate progression
or expansion of cysts. We have developed mice with kidney principal (PC) cell-specific inactivation of Tsc1
or Tsc2 genes (Published and Prelim. Data) which recapitulate the human TSC cystic kidney disease. The
cyst epithelia display few PC cells, but robust presence of A-intercalated (A-IC) cells.
 RNA-seq and confirmatory expression studies demonstrated a significant increase in the expression of
Foxi1, a transcription factor critical to the development of IC cells and activation of H+-ATPase and carbonic
anhydrase II (CAII) in Tsc1 KO mice. Double immunofluorescent labeling studies with antibodies against
H+-ATPase and AQP2; H+-ATPase and PCNA (proliferative nuclear cell antigen, a marker of cell
proliferation) and H+-ATPase and CAII demonstrated progressive loss of PC cells and hyperproliferation
of A-IC cells in cyst epithelium in Tsc1 KO mice. In addition, the electrogenic 2Cl-/H+ exchanger CLC-5,
which colocalizes with H+-ATPase in membranes of late endosomes and lysosomes under basal conditions,
demonstrated remarkable co-localization with H+-ATPase on the apical membrane of cyst epithelia in Tsc1
KO mice. Further, our results indicated the co-localization of pro-renin receptor PRR, a critical player in
Wnt signaling pathway, with H+-ATPase on the apical membrane of cyst epithelia. These changes are
distinct from those in autosomal dominant PKD cysts (Prelim Data).
 Deletion of Foxi1 in Tsc1 KO mice resulted in complete abrogation of cyst burden in Foxi1/Tsc1 double
mutant mice. In addition, deletion of CAII, which is regulated by Foxi1 and is critical to H+-ATPase activity,
significantly blunted the cyst burden in CAII/Tsc1 double mutant mice.
 We propose that the robust proliferation of A-intercalated cells and their acid/base/electrolyte transport
machinery are crucial to kidney cystogenesis in Tsc1 KO mice. We further propose that unlike cysts in PKD,
which respond to AVP V2 receptor antagonism by reduction in their fluid secretion and size, TSC cysts,
which have few principal cells, will be resistant to V2 receptor antagonists.
 To test our hypotheses, we propose to: Ascertain the role of A-IC cells and their acid base transport
machinery (H+-ATPase and CAII) in the growth and expansion of cysts in TSC disease; Determine the role
of CLC-5 and CFTR in chloride secretion into cyst lumen and cyst expansion in mice with TSC; and Examine
the effect of inhibitors of CAII/H+-ATPase, PRR and mTOR on cyst growth in TSC mice. To t...

## Key facts

- **NIH application ID:** 10874455
- **Project number:** 5I01BX001000-12
- **Recipient organization:** ALBUQUERQUE VA MEDICAL CENTER
- **Principal Investigator:** MANOOCHER SOLEIMANI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-01-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874455

## Citation

> US National Institutes of Health, RePORTER application 10874455, The Role of Intercalated Cells and Their Acid Base and Electrolyte Transport Machinery in Kidney Cystogenesis by Tuberous Sclerosis (5I01BX001000-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10874455. Licensed CC0.

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