Tuberous sclerosis complex (
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 the enlargement of benign
tumors (angiomyolipomata) and
cysts, which eventually leads to
kidney failure. The factors promoting
cyst formation and
tumor growth in
TSC are incompletely understood. Here, we report that mice with principal cell-specific inactivation of Tsc1 develop numerous cortical
cysts, which are overwhelmingly composed of hyperproliferating A-intercalated (A-IC) cells.
RNA sequencing and confirmatory expression studies demonstrated robust expression of
Forkhead Transcription Factor 1 (Foxi1) and its downstream targets, apical
H+-ATPase and cytoplasmic
carbonic anhydrase 2 (CAII), in
cyst epithelia in Tsc1 knockout (KO) mice but not in Pkd1 mutant mice. In addition, the electrogenic 2Cl-/H+ exchanger (CLC-5) is significantly up-regulated and shows remarkable colocalization with
H+-ATPase on the apical membrane of
cyst epithelia in Tsc1 KO mice. Deletion of Foxi1, which is vital to intercalated cells viability and
H+-ATPase expression, completely abrogated the
cyst burden in Tsc1 KO mice, as indicated by MRI images and histological analysis in kidneys of Foxi1/Tsc1 double-knockout (dKO) mice. Deletion of CAII, which is critical to
H+-ATPase activation, caused significant reduction in
cyst burden and increased life expectancy in CAII/Tsc1 dKO mice vs. Tsc1 KO mice. We propose that intercalated cells and their
acid/base/
electrolyte transport machinery (
H+-ATPase/CAII/CLC-5) are critical to cystogenesis, and their inhibition or inactivation is associated with significant protection against
cyst generation and/or enlargement in
TSC.