Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex

Significance Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2 gene and affects multiple organs, including the kidney, where it presents with angiomyolipomata and cysts that can result in kidney failure. The factors promoting cyst formation and tumor growth in TSC are incompletely understood. Current studies demonstrate that kidney cyst epithelia in TSC mouse models and in humans with TSC are composed of hyperproliferating intercalated cells, along with activation of H + -ATPase and carbonic anhydrase 2. Interfering with intercalated cell proliferation completely inhibited and inactivating carbonic anhydrase 2 significantly protected against cyst formation in TSC. Targeting the acid base and/or electrolyte transporters of intercalated cells may provide a therapeutic approach for the treatment of kidney cysts in TSC.