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The factors promoting kidney cyst formation in TSC are poorly understood. Inactivation of carbonic anhydrase 2 (Car2) significantly reduced, whereas, deletion of Foxi1 completely abrogated the cyst burden in Tsc1 KO mice. In these studies, we contrasted the ontogeny of cyst burden in Tsc1\/Car2 dKO mice vs. Tsc1\/Foxi1 dKO mice. Compared to Tsc1 KO, the Tsc1\/Car2 dKO mice showed few small cysts at 47 days of age. However, by 110 days, the kidneys showed frequent and large cysts with overwhelming numbers of A-intercalated cells in their linings. The magnitude of cyst burden in Tsc1\/Car2 dKO mice correlated with the expression levels of Foxi1 and was proportional to mTORC1 activation. This is in stark contrast to Tsc1\/Foxi1 dKO mice, which showed a remarkable absence of kidney cysts at both 47 and 110 days of age. RNA-seq data pointed to profound upregulation of Foxi1 and kidney-collecting duct-specific H+-ATPase subunits in 110-day-old Tsc1\/Car2 dKO mice. We conclude that Car2 inactivation temporarily decreases the kidney cyst burden in Tsc1 KO mice but the cysts increase with advancing age, along with enhanced Foxi1 expression.<\/jats:p>","DOI":"10.3390\/ijms25094772","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T08:02:22Z","timestamp":1714723342000},"page":"4772","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Carbonic Anhydrase 2 Deletion Delays the Growth of Kidney Cysts Whereas Foxi1 Deletion Completely Abrogates Cystogenesis in TSC"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5710-292X","authenticated-orcid":false,"given":"Sharon","family":"Barone","sequence":"first","affiliation":[{"name":"Research Services, New Mexico Veterans Health Care System, Albuquerque, NM 87108, USA"},{"name":"Department of Medicine, Division of Nephrology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4257-5107","authenticated-orcid":false,"given":"Kamyar","family":"Zahedi","sequence":"additional","affiliation":[{"name":"Research Services, New Mexico Veterans Health Care System, Albuquerque, NM 87108, USA"},{"name":"Department of Medicine, Division of Nephrology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6582-2281","authenticated-orcid":false,"given":"Marybeth","family":"Brooks","sequence":"additional","affiliation":[{"name":"Research Services, New Mexico Veterans Health Care System, Albuquerque, NM 87108, USA"},{"name":"Department of Medicine, Division of Nephrology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4909-4469","authenticated-orcid":false,"given":"Manoocher","family":"Soleimani","sequence":"additional","affiliation":[{"name":"Research Services, New Mexico Veterans Health Care System, Albuquerque, NM 87108, USA"},{"name":"Department of Medicine, Division of Nephrology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1056\/NEJMra055323","article-title":"The tuberous sclerosis complex","volume":"355","author":"Crino","year":"2006","journal-title":"N. 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