Carbonic Anhydrase 2 Deletion Delays the Growth of Kidney Cysts Whereas Foxi1 Deletion Completely Abrogates Cystogenesis in TSC
Abstract
1. Introduction
2. Results
2.1. Effect of Car2 Deficiency on Renal Cystogenesis in Tsc1 KO Mice
2.2. Comparison of the Markers of A-IC Cells and Principal Cells (PCs) in the Kidneys of Tsc1 KO and Tsc1/Car2 dKO Mice
2.3. The Effect of Car2 Gene Ablation on the Activation of mTORC1 in Tsc1 KO Mice
2.4. Changes in the Transcriptome of Tsc1/Car2 dKO Mice at 47 and 110 Days of Age
2.5. Enrichment Analysis of RNA-Seq Results
3. Discussion
4. Materials and Methods
4.1. Generation of Tsc1 KO, Car2 KO, Fox1 KO, Tsc1/Car2 dKO, and Tsc1/Foxi1 dKO Mice
4.2. Immunohistochemical and Immunofluorescence Microscopy
4.3. RNA-Seq Analysis
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
- Crino, P.B.; Nathanson, K.L.; Henske, E.P. The tuberous sclerosis complex. N. Engl. J. Med. 2006, 355, 1345–1356. [Google Scholar] [CrossRef] [PubMed]
- Sampson, J.R.; Harris, P.C. The molecular genetics of tuberous sclerosis. Hum. Mol. Genet. 1994, 3, 1477–1480. [Google Scholar] [CrossRef] [PubMed]
- Lam, H.C.; Siroky, B.J.; Henske, E.P. Renal disease in tuberous sclerosis complex: Pathogenesis and therapy. Nat. Rev. Nephrol. 2018, 14, 704–716. [Google Scholar] [CrossRef] [PubMed]
- Henske, E.P.; Jozwiak, S.; Kingswood, J.C.; Sampson, J.R.; Thiele, E.A. Tuberous sclerosis complex. Nat. Rev. Dis. Primers 2016, 2, 16035. [Google Scholar] [CrossRef] [PubMed]
- Rakowski, S.K.; Winterkorn, E.B.; Paul, E.; Steele, D.J.; Halpern, E.F.; Thiele, E.A. Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int. 2006, 70, 1777–1782. [Google Scholar] [CrossRef] [PubMed]
- Bissler, J.J.; Batchelor, D.; Kingswood, J.C. Progress in Tuberous Sclerosis Complex Renal Disease. Crit. Rev. Oncog. 2022, 27, 35–49. [Google Scholar] [CrossRef] [PubMed]
- Onda, H.; Lueck, A.; Marks, P.W.; Warren, H.B.; Kwiatkowski, D.J. Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J. Clin. Investig. 1999, 104, 687–695. [Google Scholar] [CrossRef] [PubMed]
- Wilson, C.; Bonnet, C.; Guy, C.; Idziaszczyk, S.; Colley, J.; Humphreys, V.; Maynard, J.; Sampson, J.R.; Cheadle, J.P. Tsc1 haploinsufficiency without mammalian target of rapamycin activation is sufficient for renal cyst formation in Tsc1+/− mice. Cancer Res. 2006, 66, 7934–7938. [Google Scholar] [CrossRef]
- Barone, S.; Zahedi, K.; Brooks, M.; Henske, E.P.; Yang, Y.; Zhang, E.; Bissler, J.J.; Yu, J.J.; Soleimani, M. Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex. Proc. Natl. Acad. Sci. USA 2021, 118, e2020190118. [Google Scholar] [CrossRef]
- Bissler, J.J.; Zadjali, F.; Bridges, D.; Astrinidis, A.; Barone, S.; Yao, Y.; Redd, J.R.; Siroky, B.J.; Wang, Y.; Finley, J.T.; et al. Tuberous sclerosis complex exhibits a new renal cystogenic mechanism. Physiol. Rep. 2019, 7, e13983. [Google Scholar] [CrossRef]
- Bonsib, S.M.; Boils, C.; Gokden, N.; Grignon, D.; Gu, X.; Higgins, J.P.; Leroy, X.; McKenney, J.K.; Nasr, S.H.; Phillips, C.; et al. Tuberous sclerosis complex: Hamartin and tuberin expression in renal cysts and its discordant expression in renal neoplasms. Pathol. Res. Pract. 2016, 212, 972–979. [Google Scholar] [CrossRef] [PubMed]
- Bissler, J.J.; Christopher Kingswood, J. Renal manifestation of tuberous sclerosis complex. Am. J. Med. Genet. C Semin. Med. Genet. 2018, 178, 338–347. [Google Scholar] [CrossRef] [PubMed]
- Gallo-Bernal, S.; Kilcoyne, A.; Gee, M.S.; Paul, E. Cystic kidney disease in tuberous sclerosis complex: Current knowledge and unresolved questions. Pediatr. Nephrol. 2023, 38, 3253–3264. [Google Scholar] [CrossRef] [PubMed]
- Henske, E.P.; Rasooly, R.; Siroky, B.; Bissler, J. Tuberous sclerosis complex, mTOR, and the kidney: Report of an NIDDK-sponsored workshop. Am. J. Physiol. Renal Physiol. 2014, 306, F279–F283. [Google Scholar] [CrossRef]
- Fingar, D.C.; Blenis, J. Target of rapamycin (TOR): An integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 2004, 23, 3151–3171. [Google Scholar] [CrossRef]
- Schmelzle, T.; Hall, M.N. TOR, a central controller of cell growth. Cell 2000, 103, 253–262. [Google Scholar] [CrossRef] [PubMed]
- Yang, Q.; Guan, K.L. Expanding mTOR signaling. Cell Res. 2007, 17, 666–681. [Google Scholar] [CrossRef] [PubMed]
- Fingar, D.C.; Salama, S.; Tsou, C.; Harlow, E.; Blenis, J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 2002, 16, 1472–1487. [Google Scholar] [CrossRef] [PubMed]
- Ogmundsdottir, M.H.; Heublein, S.; Kazi, S.; Reynolds, B.; Visvalingam, S.M.; Shaw, M.K.; Goberdhan, D.C. Proton-assisted amino acid transporter PAT1 complexes with Rag GTPases and activates TORC1 on late endosomal and lysosomal membranes. PLoS ONE 2012, 7, e36616. [Google Scholar] [CrossRef]
- Sancak, Y.; Bar-Peled, L.; Zoncu, R.; Markhard, A.L.; Nada, S.; Sabatini, D.M. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 2010, 141, 290–303. [Google Scholar] [CrossRef]
- Zoncu, R.; Bar-Peled, L.; Efeyan, A.; Wang, S.; Sancak, Y.; Sabatini, D.M. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 2011, 334, 678–683. [Google Scholar] [CrossRef] [PubMed]
- Bar-Peled, L.; Sabatini, D.M. Regulation of mTORC1 by amino acids. Trends Cell Biol. 2014, 24, 400–406. [Google Scholar] [CrossRef]
- Forgac, M. Vacuolar ATPases: Rotary proton pumps in physiology and pathophysiology. Nat. Rev. Mol. Cell Biol. 2007, 8, 917–929. [Google Scholar] [CrossRef] [PubMed]
- Hinton, A.; Bond, S.; Forgac, M. V-ATPase functions in normal and disease processes. Pflügers Arch. Eur. J. Physiol. 2009, 457, 589–598. [Google Scholar] [CrossRef] [PubMed]
- Chung, C.Y.; Shin, H.R.; Berdan, C.A.; Ford, B.; Ward, C.C.; Olzmann, J.A.; Zoncu, R.; Nomura, D.K. Covalent targeting of the vacuolar H(+)-ATPase activates autophagy via mTORC1 inhibition. Nat. Chem. Biol. 2019, 15, 776–785. [Google Scholar] [CrossRef] [PubMed]
- Brown, D.; Paunescu, T.G.; Breton, S.; Marshansky, V. Regulation of the V-ATPase in kidney epithelial cells: Dual role in acid-base homeostasis and vesicle trafficking. J. Exp. Biol. 2009, 212, 1762–1772. [Google Scholar] [CrossRef]
- Gong, F.; Alzamora, R.; Smolak, C.; Li, H.; Naveed, S.; Neumann, D.; Hallows, K.R.; Pastor-Soler, N.M. Vacuolar H+-ATPase apical accumulation in kidney intercalated cells is regulated by PKA and AMP-activated protein kinase. Am. J. Physiol. Renal Physiol. 2010, 298, F1162–F1169. [Google Scholar] [CrossRef] [PubMed]
- Soleimani, M.; Rastegar, A. Pathophysiology of Renal Tubular Acidosis: Core Curriculum 2016. Am. J. Kidney Dis. 2016, 68, 488–498. [Google Scholar] [CrossRef]
- Barone, S.; Brooks, M.; Zahedi, K.; Holliday, L.S.; Bissler, J.; Yu, J.J.; Soleimani, M. Identification of an Electrogenic 2Cl(−)/H(+) Exchanger, ClC5, as a Chloride-Secreting Transporter Candidate in Kidney Cyst Epithelium in Tuberous Sclerosis. Am. J. Pathol. 2023, 193, 191–200. [Google Scholar] [CrossRef]
- Breton, S.; Alper, S.L.; Gluck, S.L.; Sly, W.S.; Barker, J.E.; Brown, D. Depletion of intercalated cells from collecting ducts of carbonic anhydrase II-deficient (CAR2 null) mice. Am. J. Physiol. 1995, 269, F761–F774. [Google Scholar] [CrossRef]
- Brion, L.P.; Suarez, C.; Saenger, P. Postnatal disappearance of type A intercalated cells in carbonic anhydrase II-deficient mice. Pediatr. Nephrol. 2001, 16, 477–481. [Google Scholar] [CrossRef] [PubMed]
- Sun, X.; Soleimani, M.; Petrovic, S. Decreased expression of Slc26a4 (Pendrin) and Slc26a7 in the kidneys of carbonic anhydrase II-deficient mice. Cell. Physiol. Biochem. 2008, 21, 95–108. [Google Scholar] [CrossRef] [PubMed]
- Kenerson, H.L.; Aicher, L.D.; True, L.D.; Yeung, R.S. Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res. 2002, 62, 5645–5650. [Google Scholar] [PubMed]
- Dixon, B.P.; Hulbert, J.C.; Bissler, J.J. Tuberous sclerosis complex renal disease. Nephron. Exp. Nephrol. 2011, 118, e15–e20. [Google Scholar] [CrossRef] [PubMed]
- Soleimani, M. Not all kidney cysts are created equal: A distinct renal cystogenic mechanism in tuberous sclerosis complex (TSC). Front. Physiol. 2023, 14, 1289388. [Google Scholar] [CrossRef] [PubMed]
- Dibble, C.C.; Elis, W.; Menon, S.; Qin, W.; Klekota, J.; Asara, J.M.; Finan, P.M.; Kwiatkowski, D.J.; Murphy, L.O.; Manning, B.D. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell 2012, 47, 535–546. [Google Scholar] [CrossRef] [PubMed]
- Garami, A.; Zwartkruis, F.J.; Nobukuni, T.; Joaquin, M.; Roccio, M.; Stocker, H.; Kozma, S.C.; Hafen, E.; Bos, J.L.; Thomas, G. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 2003, 11, 1457–1466. [Google Scholar] [CrossRef] [PubMed]
- Huang, J.; Manning, B.D. The TSC1-TSC2 complex: A molecular switchboard controlling cell growth. Biochem. J. 2008, 412, 179–190. [Google Scholar] [CrossRef] [PubMed]
- Inoki, K.; Li, Y.; Xu, T.; Guan, K.L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003, 17, 1829–1834. [Google Scholar] [CrossRef]
- Kwiatkowski, D.J.; Manning, B.D. Tuberous sclerosis: A GAP at the crossroads of multiple signaling pathways. Hum. Mol. Genet. 2005, 14, R251–R258. [Google Scholar] [CrossRef]
- Inoki, K.; Li, Y.; Zhu, T.; Wu, J.; Guan, K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 2002, 4, 648–657. [Google Scholar] [CrossRef] [PubMed]
- Ma, L.; Chen, Z.; Erdjument-Bromage, H.; Tempst, P.; Pandolfi, P.P. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005, 121, 179–193. [Google Scholar] [CrossRef]
- Potter, C.J.; Pedraza, L.G.; Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 2002, 4, 658–665. [Google Scholar] [CrossRef]
- Roux, P.P.; Ballif, B.A.; Anjum, R.; Gygi, S.P.; Blenis, J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. USA 2004, 101, 13489–13494. [Google Scholar] [CrossRef] [PubMed]
- Bonucci, M.; Kuperwasser, N.; Barbe, S.; Koka, V.; de Villeneuve, D.; Zhang, C.; Srivastava, N.; Jia, X.; Stokes, M.P.; Bienaime, F.; et al. mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division. Nat. Commun. 2020, 11, 3200. [Google Scholar] [CrossRef] [PubMed]
- Castro, A.F.; Rebhun, J.F.; Clark, G.J.; Quilliam, L.A. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J. Biol. Chem. 2003, 278, 32493–32496. [Google Scholar] [CrossRef]
- Shillingford, J.M.; Murcia, N.S.; Larson, C.H.; Low, S.H.; Hedgepeth, R.; Brown, N.; Flask, C.A.; Novick, A.C.; Goldfarb, D.A.; Kramer-Zucker, A.; et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl. Acad. Sci. USA 2006, 103, 5466–5471. [Google Scholar] [CrossRef]
- Serra, A.L.; Poster, D.; Kistler, A.D.; Krauer, F.; Raina, S.; Young, J.; Rentsch, K.M.; Spanaus, K.S.; Senn, O.; Kristanto, P.; et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med. 2010, 363, 820–829. [Google Scholar] [CrossRef]
- Bissler, J.J.; McCormack, F.X.; Young, L.R.; Elwing, J.M.; Chuck, G.; Leonard, J.M.; Schmithorst, V.J.; Laor, T.; Brody, A.S.; Bean, J.; et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N. Engl. J. Med. 2008, 358, 140–151. [Google Scholar] [CrossRef]
- Bissler, J.J.; Budde, K.; Sauter, M.; Franz, D.N.; Zonnenberg, B.A.; Frost, M.D.; Belousova, E.; Berkowitz, N.; Ridolfi, A.; Christopher Kingswood, J. Effect of everolimus on renal function in patients with tuberous sclerosis complex: Evidence from EXIST-1 and EXIST-2. Nephrol. Dial. Transplant. 2019, 34, 1000–1008. [Google Scholar] [CrossRef]
- Blomqvist, S.R.; Vidarsson, H.; Fitzgerald, S.; Johansson, B.R.; Ollerstam, A.; Brown, R.; Persson, A.E.; Bergstrom, G.G.; Enerback, S. Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1. J. Clin. Investig. 2004, 113, 1560–1570. [Google Scholar] [CrossRef] [PubMed]
- Kui, M.; Pluznick, J.L.; Zaidman, N.A. The transcription factor Foxi1 promotes expression of V-ATPase and Gpr116 in M-1 cells. Am. J. Physiol. Renal Physiol. 2023, 324, F267–F273. [Google Scholar] [CrossRef] [PubMed]
- Lewis, S.E.; Erickson, R.P.; Barnett, L.B.; Venta, P.J.; Tashian, R.E. N-ethyl-N-nitrosourea-induced null mutation at the mouse Car-2 locus: An animal model for human carbonic anhydrase II deficiency syndrome. Proc. Natl. Acad. Sci. USA 1988, 85, 1962–1966. [Google Scholar] [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Barone, S.; Zahedi, K.; Brooks, M.; Soleimani, M. Carbonic Anhydrase 2 Deletion Delays the Growth of Kidney Cysts Whereas Foxi1 Deletion Completely Abrogates Cystogenesis in TSC. Int. J. Mol. Sci. 2024, 25, 4772. https://doi.org/10.3390/ijms25094772
Barone S, Zahedi K, Brooks M, Soleimani M. Carbonic Anhydrase 2 Deletion Delays the Growth of Kidney Cysts Whereas Foxi1 Deletion Completely Abrogates Cystogenesis in TSC. International Journal of Molecular Sciences. 2024; 25(9):4772. https://doi.org/10.3390/ijms25094772
Chicago/Turabian StyleBarone, Sharon, Kamyar Zahedi, Marybeth Brooks, and Manoocher Soleimani. 2024. "Carbonic Anhydrase 2 Deletion Delays the Growth of Kidney Cysts Whereas Foxi1 Deletion Completely Abrogates Cystogenesis in TSC" International Journal of Molecular Sciences 25, no. 9: 4772. https://doi.org/10.3390/ijms25094772
APA StyleBarone, S., Zahedi, K., Brooks, M., & Soleimani, M. (2024). Carbonic Anhydrase 2 Deletion Delays the Growth of Kidney Cysts Whereas Foxi1 Deletion Completely Abrogates Cystogenesis in TSC. International Journal of Molecular Sciences, 25(9), 4772. https://doi.org/10.3390/ijms25094772