Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Novel Potential Therapeutic Targets in Autosomal Dominant Polycystic Kidney Disease from the Perspective of Cell Polarity and Fibrosis

  • Yejin Ahn (Department of Biological Sciences, Sookmyung Women's University) ;
  • Jong Hoon Park (Department of Biological Sciences, Sookmyung Women's University)
  • Received : 2023.11.27
  • Accepted : 2023.12.26
  • Published : 2024.05.01
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Abstract

Autosomal dominant polycystic kidney disease (ADPKD), a congenital genetic disorder, is a notable contributor to the prevalence of chronic kidney disease worldwide. Despite the absence of a complete cure, ongoing research aims for early diagnosis and treatment. Although agents such as tolvaptan and mTOR inhibitors have been utilized, their effectiveness in managing the disease during its initial phase has certain limitations. This review aimed to explore new targets for the early diagnosis and treatment of ADPKD, considering ongoing developments. We particularly focus on cell polarity, which is a key factor that influences the process and pace of cyst formation. In addition, we aimed to identify agents or treatments that can prevent or impede the progression of renal fibrosis, ultimately slowing its trajectory toward end-stage renal disease. Recent advances in slowing ADPKD progression have been examined, and potential therapeutic approaches targeting multiple pathways have been introduced. This comprehensive review discusses innovative strategies to address the challenges of ADPKD and provides valuable insights into potential avenues for its prevention and treatment.

Keywords

Acknowledgement

This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (NRF-2022M3A9B6082667 and 2022R1A2C3002899).

References

  1. Arkhipov, S. N. and Pavlov, T. S. (2019) ATP release into ADPKD cysts via pannexin-1/P2X7 channels decreases ENaC activity. Biochem. Biophys. Res. Commun. 513, 166-171. https://doi.org/10.1016/j.bbrc.2019.03.177
  2. Arkhipov, S. N., Potter, D. L., Sultanova, R. F., Ilatovskaya, D. V., Harris, P. C. and Pavlov, T. S. (2023) Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease. Physiol. Rep. 11, e15652.
  3. Bellos, I. (2021) Safety profile of tolvaptan in the treatment of autosomal dominant polycystic kidney disease. Ther. Clin. Risk Manag. 17, 649-656. https://doi.org/10.2147/TCRM.S286952
  4. Berl, T. (2015) Vasopressin antagonists. N. Engl. J. Med. 373, 981.
  5. Bhalla-Gehi, R., Penuela, S., Churko, J. M., Shao, Q. and Laird, D. W. (2010) Pannexin1 and pannexin3 delivery, cell surface dynamics, and cytoskeletal interactions. J. Biol. Chem. 285, 9147-9160. https://doi.org/10.1074/jbc.M109.082008
  6. Bhalla, V. and Hallows, K. R. (2008) Mechanisms of ENaC regulation and clinical implications. J. Am. Soc. Nephrol. 19, 1845-1854. https://doi.org/10.1681/ASN.2008020225
  7. Black, P. and Sutton, R. (2013) Commentary on: tolvaptan in patients with autosomal-dominant polycystic kidney disease. Urology 81, 705-706. https://doi.org/10.1016/j.urology.2012.12.002
  8. Blazer-Yost, B. L., Esterman, M. A. and Vlahos, C. J. (2003) Insulin-stimulated trafficking of ENaC in renal cells requires PI 3-kinase activity. Am. J. Physiol. Cell Physiol. 284, C1645-C1653. https://doi.org/10.1152/ajpcell.00372.2002
  9. Borges, C. M., Fujihara, C. K., Malheiros, D., de Avila, V. F., Formigari, G. P. and Lopes de Faria, J. B. (2020) Metformin arrests the progression of established kidney disease in the subtotal nephrectomy model of chronic kidney disease. Am. J. Physiol. Renal Physiol. 318, F1229-F1236. https://doi.org/10.1152/ajprenal.00539.2019
  10. Braun, W. E., Schold, J. D., Stephany, B. R., Spirko, R. A. and Herts, B. R. (2014) Low-dose rapamycin (sirolimus) effects in autosomal dominant polycystic kidney disease: an open-label randomized controlled pilot study. Clin. J. Am. Soc. Nephrol. 9, 881-888. https://doi.org/10.2215/CJN.02650313
  11. Bulow, R. D. and Boor, P. (2019) Extracellular matrix in kidney fibrosis: more than just a scaffold. J. Histochem. Cytochem. 67, 643-661. https://doi.org/10.1369/0022155419849388
  12. Calvet, J. P. (1993) Polycystic kidney disease: primary extracellular matrix abnormality or defective cellular differentiation? Kidney Int. 43, 101-108. https://doi.org/10.1038/ki.1993.17
  13. Cameron, K. O., Kung, D. W., Kalgutkar, A. S., Kurumbail, R. G., Miller, R., Salatto, C. T., Ward, J., Withka, J. M., Bhattacharya, S. K., Boehm, M., Borzilleri, K. A., Brown, J. A., Calabrese, M., Caspers, N. L., Cokorinos, E., Conn, E. L., Dowling, M. S., Edmonds, D. J., Eng, H., Fernando, D. P., Frisbie, R., Hepworth, D., Landro, J., Mao, Y., Rajamohan, F., Reyes, A. R., Rose, C. R., Ryder, T., Shavnya, A., Smith, A. C., Tu, M., Wolford, A. C. and Xiao, J. (2016) Discovery and preclinical characterization of 6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid (PF-06409577), a direct activator of adenosine monophosphate-activated protein kinase (AMPK), for the potential treatment of diabetic nephropathy. J. Med. Chem. 59, 8068-8081. https://doi.org/10.1021/acs.jmedchem.6b00866
  14. Cebotaru, L., Liu, Q., Yanda, M. K., Boinot, C., Outeda, P., Huso, D. L., Watnick, T., Guggino, W. B. and Cebotaru, V. (2016) Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease. Kidney Int. 90, 90-99. https://doi.org/10.1016/j.kint.2016.01.026
  15. Chebib, F. T., Perrone, R. D., Chapman, A. B., Dahl, N. K., Harris, P. C., Mrug, M., Mustafa, R. A., Rastogi, A., Watnick, T., Yu, A. S. L. and Torres, V. E. (2018) A practical guide for treatment of rapidly progressive ADPKD with tolvaptan. J. Am. Soc. Nephrol. 29, 2458-2470. https://doi.org/10.1681/ASN.2018060590
  16. Chebib, F. T. and Torres, V. E. (2016) Autosomal dominant polycystic kidney disease: core curriculum 2016. Am. J. Kidney Dis. 67, 792-810. https://doi.org/10.1053/j.ajkd.2015.07.037
  17. Chiang, C. W., Lee, H. T., Tarng, D. C., Kuo, K. L., Cheng, L. C. and Lee, T. S. (2015) Genetic deletion of soluble epoxide hydrolase attenuates inflammation and fibrosis in experimental obstructive nephropathy. Mediators Inflamm. 2015, 693260.
  18. Chiu, Y. H., Schappe, M. S., Desai, B. N. and Bayliss, D. A. (2018) Revisiting multimodal activation and channel properties of Pannexin 1. J. Gen. Physiol. 150, 19-39. https://doi.org/10.1085/jgp.201711888
  19. Chow, C. L. and Ong, A. C. (2009) Autosomal dominant polycystic kidney disease. Clin. Med. (Lond.) 9, 278-283. https://doi.org/10.7861/clinmedicine.9-3-278
  20. Dagorn, P. G., Buchholz, B., Kraus, A., Batchuluun, B., Bange, H., Blockken, L., Steinberg, G. R., Moller, D. E. and Hallakou-Bozec, S. (2023) A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease. Kidney Int. 103, 917-929. https://doi.org/10.1016/j.kint.2023.01.026
  21. Esquejo, R. M., Salatto, C. T., Delmore, J., Albuquerque, B., Reyes, A., Shi, Y., Moccia, R., Cokorinos, E., Peloquin, M., Monetti, M., Barricklow, J., Bollinger, E., Smith, B. K., Day, E. A., Nguyen, C., Geoghegan, K. F., Kreeger, J. M., Opsahl, A., Ward, J., Kalgutkar, A. S., Tess, D., Butler, L., Shirai, N., Osborne, T. F., Steinberg, G. R., Birnbaum, M. J., Cameron, K. O. and Miller, R. A. (2018) Activation of liver AMPK with PF-06409577 corrects NAFLD and lowers cholesterol in rodent and primate preclinical models. EBioMedicine 31, 122-132. https://doi.org/10.1016/j.ebiom.2018.04.009
  22. Falke, L. L., Gholizadeh, S., Goldschmeding, R., Kok, R. J. and Nguyen, T. Q. (2015) Diverse origins of the myofibroblast-implications for kidney fibrosis. Nat. Rev. Nephrol. 11, 233-244. https://doi.org/10.1038/nrneph.2014.246
  23. Feng, L., Li, W., Chao, Y., Huan, Q., Lu, F., Yi, W., Jun, W., Binbin, C., Na, L. and Shougang, Z. (2021) Synergistic inhibition of renal fibrosis by nintedanib and gefitinib in a murine model of obstructive nephropathy. Kidney Dis. (Basel) 7, 34-49. https://doi.org/10.1159/000509670
  24. Feng, Y., Huang, R., Guo, F., Liang, Y., Xiang, J., Lei, S., Shi, M., Li, L., Liu, J., Feng, Y., Ma, L. and Fu, P. (2018) Selective histone deacetylase 6 inhibitor 23BB alleviated rhabdomyolysis-induced acute kidney injury by regulating endoplasmic reticulum stress and apoptosis. Front. Pharmacol. 9, 274.
  25. Fragiadaki, M., Macleod, F. M. and Ong, A. C. M. (2020) The controversial role of fibrosis in autosomal dominant polycystic kidney disease. Int. J. Mol. Sci. 21, 8936.
  26. Fujiki, T., Ando, F., Murakami, K., Isobe, K., Mori, T., Susa, K., Nomura, N., Sohara, E., Rai, T. and Uchida, S. (2019) Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation. Sci. Rep. 9, 9245.
  27. Gai, Z., Chu, L., Xu, Z., Song, X., Sun, D. and Kullak-Ublick, G. A. (2017) Farnesoid X receptor activation protects the kidney from ischemia-reperfusion damage. Sci. Rep. 7, 9815.
  28. Garcia-Caballero, A., Rasmussen, J. E., Gaillard, E., Watson, M. J., Olsen, J. C., Donaldson, S. H., Stutts, M. J. and Tarran, R. (2009) SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage. Proc. Natl. Acad. Sci. U. S. A. 106, 11412-11417. https://doi.org/10.1073/pnas.0903609106
  29. Gluais-Dagorn, P., Foretz, M., Steinberg, G. R., Batchuluun, B., Zawistowska-Deniziak, A., Lambooij, J. M., Guigas, B., Carling, D., Monternier, P. A., Moller, D. E., Bolze, S. and Hallakou-Bozec, S. (2022) Direct AMPK activation corrects NASH in rodents through metabolic effects and direct action on inflammation and fibrogenesis. Hepatol. Commun. 6, 101-119. https://doi.org/10.1002/hep4.1799
  30. Gluba-Sagr, A., Franczyk, B., Rysz-Gorzynska, M., Lawinski, J. and Rysz, J. (2023) The role of miRNA in renal fibrosis leading to chronic kidney disease. Biomedicines 11, 2358.
  31. Grantham, J. J., Cook, L. T., Torres, V. E., Bost, J. E., Chapman, A. B., Harris, P. C., Guay-Woodford, L. M. and Bae, K. T. (2008) Determinants of renal volume in autosomal-dominant polycystic kidney disease. Kidney Int. 73, 108-116. https://doi.org/10.1038/sj.ki.5002624
  32. Hao, Y., Guo, F., Huang, Z., Feng, Y., Xia, Z., Liu, J., Li, L., Huang, R., Lin, L., Ma, L. and Fu, P. (2020) 2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury. Biosci. Rep. 40, BSR20191538.
  33. Holditch, S. J., Brown, C. N., Atwood, D. J., Lombardi, A. M., Nguyen, K. N., Toll, H. W., Hopp, K. and Edelstein, C. L. (2019) A study of sirolimus and mTOR kinase inhibitor in a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease. Am. J. Physiol. Renal Physiol. 317, F187-F196. https://doi.org/10.1152/ajprenal.00051.2019
  34. Hori, M. (2013) Tolvaptan for the treatment of hyponatremia and hypervolemia in patients with congestive heart failure. Future Cardiol. 9, 163-176. https://doi.org/10.2217/fca.13.3
  35. Hye Khan, M. A., Schmidt, J., Stavniichuk, A., Imig, J. D. and Merk, D. (2019) A dual farnesoid X receptor/soluble epoxide hydrolase modulator treats non-alcoholic steatohepatitis in mice. Biochem. Pharmacol. 166, 212-221. https://doi.org/10.1016/j.bcp.2019.05.023
  36. Imig, J. D., Merk, D. and Proschak, E. (2021) Multi-target drugs for kidney diseases. Kidney360 2, 1645-1653. https://doi.org/10.34067/KID.0003582021
  37. Jamadar, A., Suma, S. M., Mathew, S., Fields, T. A., Wallace, D. P., Calvet, J. P. and Rao, R. (2021) The tyrosine-kinase inhibitor Nintedanib ameliorates autosomal-dominant polycystic kidney disease. Cell Death Dis. 12, 947.
  38. Karner, C., Wharton, K. A., Jr. and Carroll, T. J. (2006) Planar cell polarity and vertebrate organogenesis. Semin. Cell Dev. Biol. 17, 194-203. https://doi.org/10.1016/j.semcdb.2006.05.003
  39. Kato, T., Hagiyama, M. and Ito, A. (2018) Renal ADAM10 and 17: their physiological and medical meanings. Front. Cell Dev. Biol. 6, 153.
  40. Ke, B., Chen, Y., Tu, W., Ye, T., Fang, X. and Yang, L. (2018) Inhibition of HDAC6 activity in kidney diseases: a new perspective. Mol. Med. 24, 33.
  41. Kim, J., Yoon, S. P., Toews, M. L., Imig, J. D., Hwang, S. H., Hammock, B. D. and Padanilam, B. J. (2015) Pharmacological inhibition of soluble epoxide hydrolase prevents renal interstitial fibrogenesis in obstructive nephropathy. Am. J. Physiol. Renal Physiol. 308, F131-F139. https://doi.org/10.1152/ajprenal.00531.2014
  42. Kong, T., Xu, D., Yu, W., Takakura, A., Boucher, I., Tran, M., Kreidberg, J. A., Shah, J., Zhou, J. and Denker, B. M. (2009) G alpha 12 inhibits alpha2 beta1 integrin-mediated Madin-Darby canine kidney cell attachment and migration on collagen-I and blocks tubulogenesis. Mol. Biol. Cell 20, 4596-4610. https://doi.org/10.1091/mbc.e09-03-0220
  43. Kunimoto, K., Bayly, R. D., Vladar, E. K., Vonderfecht, T., Gallagher, A. R. and Axelrod, J. D. (2017) Disruption of core planar cell polarity signaling regulates renal tubule morphogenesis but is not cystogenic. Curr. Biol. 27, 3120-3131.e4. https://doi.org/10.1016/j.cub.2017.09.011
  44. Lanke, S. and Shoaf, S. E. (2019) Population pharmacokinetic analyses and model validation of tolvaptan in subjects with autosomal dominant polycystic kidney disease. J. Clin. Pharmacol. 59, 763-770. https://doi.org/10.1002/jcph.1370
  45. Le Corre, S., Viau, A., Burtin, M., El-Karoui, K., Cnops, Y., Terryn, S., Debaix, H., Berissi, S., Gubler, M. C., Devuyst, O. and Terzi, F. (2015) Cystic gene dosage influences kidney lesions after nephron reduction. Nephron 129, 42-51. https://doi.org/10.1159/000369312
  46. Lee, M., Katerelos, M., Gleich, K., Galic, S., Kemp, B. E., Mount, P. F. and Power, D. A. (2018) Phosphorylation of acetyl-CoA carboxylase by AMPK reduces renal fibrosis and is essential for the antifibrotic effect of metformin. J. Am. Soc. Nephrol. 29, 2326-2336. https://doi.org/10.1681/ASN.2018010050
  47. Liang, D., Song, Z., Liang, W., Li, Y. and Liu, S. (2019) Metformin inhibits TGF-beta 1-induced MCP-1 expression through BAMBI-mediated suppression of MEK/ERK1/2 signalling. Nephrology (Carlton) 24, 481-488. https://doi.org/10.1111/nep.13430
  48. Lichtenthaler, S. F., Lemberg, M. K. and Fluhrer, R. (2018) Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments. EMBO J. 37, e99456.
  49. Liu, F., Wang, L., Qi, H., Wang, J., Wang, Y., Jiang, W., Xu, L., Liu, N. and Zhuang, S. (2017) Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease. Clin. Sci. (Lond.) 131, 2125-2143. https://doi.org/10.1042/CS20170134
  50. Liu, F. and Zhuang, S. (2016) Role of receptor tyrosine kinase signaling in renal fibrosis. Int. J. Mol. Sci. 17, 972.
  51. Liu, W., Fan, L. X., Zhou, X., Sweeney, W. E., Jr., Avner, E. D. and Li, X. (2012) HDAC6 regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation in renal epithelial cells. PLoS One 7, e49418.
  52. Liu, Y., Pejchinovski, M., Wang, X., Fu, X., Castelletti, D., Watnick, T. J., Arcaro, A., Siwy, J., Mullen, W., Mischak, H. and Serra, A. L. (2018) Dual mTOR/PI3K inhibition limits PI3K-dependent pathways activated upon mTOR inhibition in autosomal dominant polycystic kidney disease. Sci. Rep. 8, 5584.
  53. Lorenz, M. C. and Heitman, J. (1995) TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin. J. Biol. Chem. 270, 27531-27537. https://doi.org/10.1074/jbc.270.46.27531
  54. Lorenzo Pisarello, M., Masyuk, T. V., Gradilone, S. A., Masyuk, A. I., Ding, J. F., Lee, P. Y. and LaRusso, N. F. (2018) Combination of a histone deacetylase 6 inhibitor and a somatostatin receptor agonist synergistically reduces hepatorenal cystogenesis in an animal model of polycystic liver disease. Am. J. Pathol. 188, 981-994. https://doi.org/10.1016/j.ajpath.2017.12.016
  55. Luyten, A., Su, X., Gondela, S., Chen, Y., Rompani, S., Takakura, A. and Zhou, J. (2010) Aberrant regulation of planar cell polarity in polycystic kidney disease. J. Am. Soc. Nephrol. 21, 1521-1532. https://doi.org/10.1681/ASN.2010010127
  56. Mangolini, A., de Stephanis, L. and Aguiari, G. (2016) Role of calcium in polycystic kidney disease: from signaling to pathology. World J. Nephrol. 5, 76-83. https://doi.org/10.5527/wjn.v5.i1.76
  57. Maretzky, T., Reiss, K., Ludwig, A., Buchholz, J., Scholz, F., Proksch, E., de Strooper, B., Hartmann, D. and Saftig, P. (2005) ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. Proc. Natl. Acad. Sci. U. S. A. 102, 9182-9187. https://doi.org/10.1073/pnas.0500918102
  58. McCarty, M. F., Barroso-Aranda, J. and Contreras, F. (2009) Activation of AMP-activated kinase as a strategy for managing autosomal dominant polycystic kidney disease. Med. Hypotheses 73, 1008-1010. https://doi.org/10.1016/j.mehy.2009.05.043
  59. Mekahli, D., Decuypere, J. P., Sammels, E., Welkenhuyzen, K., Schoeber, J., Audrezet, M. P., Corvelyn, A., Dechenes, G., Ong, A. C., Wilmer, M. J., van den Heuvel, L., Bultynck, G., Parys, J. B., Missiaen, L., Levtchenko, E. and De Smedt, H. (2014) Polycystin-1 but not polycystin-2 deficiency causes upregulation of the mTOR pathway and can be synergistically targeted with rapamycin and metformin. Pflugers Arch. 466, 1591-1604.
  60. Meyer-Schwesinger, C., Seipold, L. and Saftig, P. (2022) Ectodomain shedding by ADAM proteases as a central regulator in kidney physiology and disease. Biochim. Biophys. Acta Mol. Cell Res. 1869, 119165.
  61. Milazzo, G., Mercatelli, D., Di Muzio, G., Triboli, L., De Rosa, P., Perini, G. and Giorgi, F. M. (2020) Histone deacetylases (HDACs): evolution, specificity, role in transcriptional complexes, and pharmacological actionability. Genes (Basel) 11, 556.
  62. Nakamura, M., Sunagawa, O. and Kinugawa, K. (2018) Tolvaptan improves prognosis in responders with acute decompensated heart failure by reducing the dose of loop diuretics. Int. Heart J. 59, 87-93. https://doi.org/10.1536/ihj.17-099
  63. Nigro, E. A., Castelli, M. and Boletta, A. (2015) Role of the polycystins in cell migration, polarity, and tissue morphogenesis. Cells 4, 687-705. https://doi.org/10.3390/cells4040687
  64. Norman, J. (2011) Fibrosis and progression of autosomal dominant polycystic kidney disease (ADPKD). Biochim. Biophys. 1812, 1327-1336. https://doi.org/10.1016/j.bbadis.2011.06.012
  65. Oh, Y. K., Park, H. C., Ryu, H., Kim, Y. C. and Oh, K. H. (2021) Clinical and genetic characteristics of Korean autosomal dominant polycystic kidney disease patients. Korean J. Intern. Med. 36, 767-779. https://doi.org/10.3904/kjim.2021.176
  66. Papakrivopoulou, E., Jafree, D. J., Dean, C. H. and Long, D. A. (2021) The biological significance and implications of planar cell polarity for nephrology. Front. Physiol. 12, 599529.
  67. Pastor-Soler, N. M., Li, H., Pham, J., Rivera, D., Ho, P. Y., Mancino, V., Saitta, B. and Hallows, K. R. (2022) Metformin improves relevant disease parameters in an autosomal dominant polycystic kidney disease mouse model. Am. J. Physiol. Renal Physiol. 322, F27-F41. https://doi.org/10.1152/ajprenal.00298.2021
  68. Pathomthongtaweechai, N., Soodvilai, S., Chatsudthipong, V. and Muanprasat, C. (2014) Pranlukast inhibits renal epithelial cyst progression via activation of AMP-activated protein kinase. Eur. J. Pharmacol. 724, 67-76. https://doi.org/10.1016/j.ejphar.2013.12.013
  69. Perico, N., Antiga, L., Caroli, A., Ruggenenti, P., Fasolini, G., Cafaro, M., Ondei, P., Rubis, N., Diadei, O., Gherardi, G., Prandini, S., Panozo, A., Bravo, R. F., Carminati, S., De Leon, F. R., Gaspari, F., Cortinovis, M., Motterlini, N., Ene-Iordache, B., Remuzzi, A. and Remuzzi, G. (2010) Sirolimus therapy to halt the progression of ADPKD. J. Am. Soc. Nephrol. 21, 1031-1040. https://doi.org/10.1681/ASN.2009121302
  70. Pulya, S., Amin, S. A., Adhikari, N., Biswas, S., Jha, T. and Ghosh, B. (2021) HDAC6 as privileged target in drug discovery: a perspective. Pharmacol. Res. 163, 105274.
  71. Raina, R., Chakraborty, R., DeCoy, M. E. and Kline, T. (2021) Autosomal-dominant polycystic kidney disease: tolvaptan use in adolescents and young adults with rapid progression. Pediatr. Res. 89, 894-899. https://doi.org/10.1038/s41390-020-0942-2
  72. Riga, A., Castiglioni, V. G. and Boxem, M. (2020) New insights into apical-basal polarization in epithelia. Curr. Opin. Cell Biol. 62, 1-8. https://doi.org/10.1016/j.ceb.2019.07.017
  73. Rockey, D. C., Bell, P. D. and Hill, J. A. (2015) Fibrosis--a common pathway to organ injury and failure. N. Engl. J. Med. 372, 1138-1149. https://doi.org/10.1056/NEJMra1300575
  74. Roitbak, T., Ward, C. J., Harris, P. C., Bacallao, R., Ness, S. A. and Wandinger-Ness, A. (2004) A polycystin-1 multiprotein complex is disrupted in polycystic kidney disease cells. Mol. Biol. Cell 15, 1334-1346. https://doi.org/10.1091/mbc.e03-05-0296
  75. Sabers, C. J., Martin, M. M., Brunn, G. J., Williams, J. M., Dumont, F. J., Wiederrecht, G. and Abraham, R. T. (1995) Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J. Biol. Chem. 270, 815-822. https://doi.org/10.1074/jbc.270.2.815
  76. Satriano, J., Sharma, K., Blantz, R. C. and Deng, A. (2013) Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease. Am. J. Physiol. Renal Physiol. 305, F727-F733. https://doi.org/10.1152/ajprenal.00293.2013
  77. Schonauer, R., Baatz, S., Nemitz-Kliemchen, M., Frank, V., Petzold, F., Sewerin, S., Popp, B., Munch, J., Neuber, S., Bergmann, C. and Halbritter, J. (2020) Matching clinical and genetic diagnoses in autosomal dominant polycystic kidney disease reveals novel phenocopies and potential candidate genes. Genet. Med. 22, 1374-1383. https://doi.org/10.1038/s41436-020-0816-3
  78. Seliger, S. L., Abebe, K. Z., Hallows, K. R., Miskulin, D. C., Perrone, R. D., Watnick, T. and Bae, K. T. (2018) A randomized clinical trial of metformin to treat autosomal dominant polycystic kidney disease. Am. J. Nephrol. 47, 352-360. https://doi.org/10.1159/000488807
  79. Serra, A. L., Poster, D., Kistler, A. D., Krauer, F., Raina, S., Young, J., Rentsch, K. M., Spanaus, K. S., Senn, O., Kristanto, P., Scheffel, H., Weishaupt, D. and Wuthrich, R. P. (2010) Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 820-829. https://doi.org/10.1056/NEJMoa0907419
  80. Seto, E. and Yoshida, M. (2014) Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6, a018713.
  81. Sharma, M., Reif, G. A. and Wallace, D. P. (2019) In vitro cyst formation of ADPKD cells. Methods Cell Biol. 153, 93-111. https://doi.org/10.1016/bs.mcb.2019.05.008
  82. Sharma, S. and Smyth, B. (2021) From proteinuria to fibrosis: an update on pathophysiology and treatment options. Kidney Blood Press. Res. 46, 411-420. https://doi.org/10.1159/000516911
  83. Shillingford, J. M., Leamon, C. P., Vlahov, I. R. and Weimbs, T. (2012) Folate-conjugated rapamycin slows progression of polycystic kidney disease. J. Am. Soc. Nephrol. 23, 1674-1681. https://doi.org/10.1681/ASN.2012040367
  84. 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., Walz, G., Piontek, K. B., Germino, G. G. and Weimbs, T. (2006) The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl. Acad. Sci. U. S. A. 103, 5466-5471. https://doi.org/10.1073/pnas.0509694103
  85. Shillingford, J. M., Piontek, K. B., Germino, G. G. and Weimbs, T. (2010) Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J. Am. Soc. Nephrol. 21, 489-497. https://doi.org/10.1681/ASN.2009040421
  86. Shiu, J. S., Hsieh, M. J., Chiou, H. L., Wang, H. L., Yeh, C. B., Yang, S. F. and Chou, Y. E. (2018) Impact of ADAM10 gene polymorphisms on hepatocellular carcinoma development and clinical characteristics. Int. J. Med. Sci. 15, 1334-1340. https://doi.org/10.7150/ijms.27059
  87. Shum, M. G., Shao, Q., Lajoie, P. and Laird, D. W. (2019) Destination and consequences of Panx1 and mutant expression in polarized MDCK cells. Exp. Cell Res. 381, 235-247. https://doi.org/10.1016/j.yexcr.2019.05.016
  88. Silberberg, M., Charron, A. J., Bacallao, R. and Wandinger-Ness, A. (2005) Mispolarization of desmosomal proteins and altered intercellular adhesion in autosomal dominant polycystic kidney disease. Am. J. Physiol. Renal Physiol. 288, F1153-F1163. https://doi.org/10.1152/ajprenal.00008.2005
  89. Silverman, W., Locovei, S. and Dahl, G. (2008) Probenecid, a gout remedy, inhibits pannexin 1 channels. Am. J. Physiol. Cell Physiol. 295, C761-C767. https://doi.org/10.1152/ajpcell.00227.2008
  90. Solanas, G., Cortina, C., Sevillano, M. and Batlle, E. (2011) Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling. Nat. Cell Biol. 13, 1100-1107. https://doi.org/10.1038/ncb2298
  91. Song, A., Zhang, C. and Meng, X. (2021) Mechanism and application of metformin in kidney diseases: an update. Biomed. Pharmacother. 138, 111454.
  92. Staruschenko, A., Pochynyuk, O., Vandewalle, A., Bugaj, V. and Stockand, J. D. (2007) Acute regulation of the epithelial Na+ channel by phosphatidylinositide 3-OH kinase signaling in native collecting duct principal cells. J. Am. Soc. Nephrol. 18, 1652-1661. https://doi.org/10.1681/ASN.2007010020
  93. Stavniichuk, A., Savchuk, O., Khan, A. H., Jankiewicz, W. K., Imig, J. D. and Merk, D. (2020) The effect of compound DM509 on kidney fibrosis in the conditions of the experimental model. Visnyk Kyivskoho Natsionalnoho Universytetu Imeni Tarasa Shevchenka Biolohiia 80, 10-15.
  94. Su, L., Yuan, H., Zhang, H., Wang, R., Fu, K., Yin, L., Ren, Y., Liu, H., Fang, Q., Wang, J. and Guo, D. (2022) PF-06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity. FEBS Open Bio 12, 1761-1770. https://doi.org/10.1002/2211-5463.13459
  95. Sudarikova, A. V., Vasileva, V. Y., Sultanova, R. F. and Ilatovskaya, D. V. (2021) Recent advances in understanding ion transport mechanisms in polycystic kidney disease. Clin. Sci. (Lond.) 135, 2521-2540. https://doi.org/10.1042/CS20210370
  96. Takiar, V., Nishio, S., Seo-Mayer, P., King, J. D., Jr., Li, H., Zhang, L., Karihaloo, A., Hallows, K. R., Somlo, S. and Caplan, M. J. (2011) Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc. Natl. Acad. Sci. U. S. A. 108, 2462-2467. https://doi.org/10.1073/pnas.1011498108
  97. Tamma, G., Di Mise, A., Ranieri, M., Geller, A., Tamma, R., Zallone, A. and Valenti, G. (2017) The V2 receptor antagonist tolvaptan raises cytosolic calcium and prevents AQP2 trafficking and function: an in vitro and in vivo assessment. J. Cell. Mol. Med. 21, 1767-1780. https://doi.org/10.1111/jcmm.13098
  98. Tan, Y. C., Blumenfeld, J. and Rennert, H. (2011) Autosomal dominant polycystic kidney disease: genetics, mutations and microRNAs. Biochim. Biophys. Acta 1812, 1202-1212. https://doi.org/10.1016/j.bbadis.2011.03.002
  99. Torres, V. E., Chapman, A. B., Devuyst, O., Gansevoort, R. T., Grantham, J. J., Higashihara, E., Perrone, R. D., Krasa, H. B., Ouyang, J. and Czerwiec, F. S.; TEMPO 3:4 Trial Investigators (2012) Tolvaptan in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 367, 2407-2418. https://doi.org/10.1056/NEJMoa1205511
  100. Torres, V. E., Devuyst, O., Chapman, A. B., Gansevoort, R. T., Perrone, R. D., Ouyang, J., Blais, J. D., Czerwiec, F. S. and Sergeyeva, O.; REPRISE Trial Investigators (2017) Rationale and design of a clinical trial investigating tolvaptan safety and efficacy in autosomal dominant polycystic kidney disease. Am. J. Nephrol. 45, 257-266. https://doi.org/10.1159/000456087
  101. Torres, V. E. and Harris, P. C. (2014) Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J. Am. Soc. Nephrol. 25, 18-32. https://doi.org/10.1681/ASN.2013040398
  102. Tran Nguyen Truc, L., Matsuda, S., Takenouchi, A., Tran Thuy Huong, Q., Kotani, Y., Miyazaki, T., Kanda, H., Yoshizawa, K. and Tsukaguchi, H. (2023) Mechanism of cystogenesis by Cd79a-driven, conditional mTOR activation in developing mouse nephrons. Sci. Rep. 13, 508.
  103. Valenzuela-Fernandez, A., Cabrero, J. R., Serrador, J. M. and Sanchez-Madrid, F. (2008) HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions. Trends Cell Biol. 18, 291-297. https://doi.org/10.1016/j.tcb.2008.04.003
  104. Vinciguerra, M., Mordasini, D., Vandewalle, A. and Feraille, E. (2005) Hormonal and nonhormonal mechanisms of regulation of the NA,K-pump in collecting duct principal cells. Semin. Nephrol. 25, 312-321. https://doi.org/10.1016/j.semnephrol.2005.03.006
  105. Wahl, P. R., Serra, A. L., Le Hir, M., Molle, K. D., Hall, M. N. and Wuthrich, R. P. (2006) Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrol. Dial. Transplant. 21, 598-604. https://doi.org/10.1093/ndt/gfi181
  106. Walz, G., Budde, K., Mannaa, M., Nurnberger, J., Wanner, C., Sommerer, C., Kunzendorf, U., Banas, B., Horl, W. H., Obermuller, N., Arns, W., Pavenstadt, H., Gaedeke, J., Buchert, M., May, C., Gschaidmeier, H., Kramer, S. and Eckardt, K. U. (2010) Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 830-840. https://doi.org/10.1056/NEJMoa1003491
  107. Wang, J. N. and Cao, X. J. (2023) Targeting ADAM10 in renal diseases. Curr. Mol. Med. 23, 1037-1045. https://doi.org/10.2174/1566524023666221020142504
  108. Wang, X. X., Jiang, T., Shen, Y., Caldas, Y., Miyazaki-Anzai, S., Santamaria, H., Urbanek, C., Solis, N., Scherzer, P., Lewis, L., Gonzalez, F. J., Adorini, L., Pruzanski, M., Kopp, J. B., Verlander, J. W. and Levi, M. (2010) Diabetic nephropathy is accelerated by farnesoid X receptor deficiency and inhibited by farnesoid X receptor activation in a type 1 diabetes model. Diabetes 59, 2916-2927. https://doi.org/10.2337/db10-0019
  109. Watkins, P. B., Lewis, J. H., Kaplowitz, N., Alpers, D. H., Blais, J. D., Smotzer, D. M., Krasa, H., Ouyang, J., Torres, V. E., Czerwiec, F. S. and Zimmer, C. A. (2015) Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database. Drug Saf. 38, 1103-1113. https://doi.org/10.1007/s40264-015-0327-3
  110. Wei, Z. Y., Qu, H. L., Dai, Y. J., Wang, Q., Ling, Z. M., Su, W. F., Zhao, Y. Y., Shen, W. X. and Chen, G. (2021) Pannexin 1, a large-pore membrane channel, contributes to hypotonicity-induced ATP release in Schwann cells. Neural Regen. Res. 16, 899-904. https://doi.org/10.4103/1673-5374.290911
  111. Whyte-Fagundes, P. and Zoidl, G. (2018) Mechanisms of pannexin1 channel gating and regulation. Biochim. Biophys. Acta Biomembr. 1860, 65-71. https://doi.org/10.1016/j.bbamem.2017.07.009
  112. Wicki-Stordeur, L. E. and Swayne, L. A. (2013) Panx1 regulates neural stem and progenitor cell behaviours associated with cytoskeletal dynamics and interacts with multiple cytoskeletal elements. Cell Commun. Signal. 11, 62.
  113. Wilson, P. D. (2011) Apico-basal polarity in polycystic kidney disease epithelia. Biochim. Biophys. Acta 1812, 1239-1248. https://doi.org/10.1016/j.bbadis.2011.05.008
  114. Wu, Y., Xu, J. X., El-Jouni, W., Lu, T., Li, S., Wang, Q., Tran, M., Yu, W., Wu, M., Barrera, I. E., Bonventre, J. V., Zhou, J., Denker, B. M. and Kong, T. (2016) Galpha12 is required for renal cystogenesis induced by Pkd1 inactivation. J. Cell Sci. 129, 3675-3684. https://doi.org/10.1242/jcs.190496
  115. Xiao, W., Pinilla-Baquero, A., Faulkner, J., Song, X., Prabhakar, P., Qiu, H., Moremen, K. W., Ludwig, A., Dempsey, P. J., Azadi, P. and Wang, L. (2022) Robo4 is constitutively shed by ADAMs from endothelial cells and the shed Robo4 functions to inhibit Slit3-induced angiogenesis. Sci. Rep. 12, 4352.
  116. Xu, D., Lv, J., He, L., Fu, L., Hu, R., Cao, Y. and Mei, C. (2018a) Scribble influences cyst formation in autosomal-dominant polycystic kidney disease by regulating Hippo signaling pathway. FASEB J. 32, 4394-4407. https://doi.org/10.1096/fj.201701376RR
  117. Xu, J. X., Lu, T. S., Li, S., Wu, Y., Ding, L., Denker, B. M., Bonventre, J. V. and Kong, T. (2015) Polycystin-1 and Galpha12 regulate the cleavage of E-cadherin in kidney epithelial cells. Physiol. Genomics 47, 24-32. https://doi.org/10.1152/physiolgenomics.00090.2014
  118. Xu, X., Wicki-Stordeur, L. E., Sanchez-Arias, J. C., Liu, M., Weaver, M. S., Choi, C. S. W. and Swayne, L. A. (2018b) Probenecid disrupts a novel pannexin 1-collapsin response mediator protein 2 interaction and increases microtubule stability. Front. Cell. Neurosci. 12, 124.
  119. Yanda, M. K., Liu, Q. and Cebotaru, L. (2017a) An inhibitor of histone deacetylase 6 activity, ACY-1215, reduces cAMP and cyst growth in polycystic kidney disease. Am. J. Physiol. Renal Physiol. 313, F997-F1004. https://doi.org/10.1152/ajprenal.00186.2017
  120. Yanda, M. K., Liu, Q., Cebotaru, V., Guggino, W. B. and Cebotaru, L. (2017b) Histone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca(2+) in knock-out mouse models of polycystic kidney disease. J. Biol. Chem. 292, 17897-17908. https://doi.org/10.1074/jbc.M117.803775
  121. Yu, W., Ritchie, B. J., Su, X., Zhou, J., Meigs, T. E. and Denker, B. M. (2011) Identification of polycystin-1 and Galpha12 binding regions necessary for regulation of apoptosis. Cell. Signal. 23, 213-221. https://doi.org/10.1016/j.cellsig.2010.09.005
  122. Yuan, Q., Tan, R. J. and Liu, Y. (2019) Myofibroblast in kidney fibrosis: origin, activation, and regulation. Adv. Exp. Med. Biol. 1165, 253-283. https://doi.org/10.1007/978-981-13-8871-2_12
  123. Yuan, Q., Yu, H., Chen, J., Song, X. and Sun, L. (2020) ADAM10 promotes cell growth, migration, and invasion in osteosarcoma via regulating E-cadherin/beta-catenin signaling pathway and is regulated by miR-122-5p. Cancer Cell Int. 20, 99.
  124. Zafar, I., Ravichandran, K., Belibi, F. A., Doctor, R. B. and Edelstein, C. L. (2010) Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease. Kidney Int. 78, 754-761. https://doi.org/10.1038/ki.2010.250
  125. Zhang, Y., Daniel, E. A., Metcalf, J., Dai, Y., Reif, G. A. and Wallace, D. P. (2022) CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation. J. Mol. Cell Biol. 14, mjac050.
  126. Zheng, W., Song, J., Zhang, Y., Chen, S., Ruan, H. and Fan, C. (2017) Metformin prevents peritendinous fibrosis by inhibiting transforming growth factor-beta signaling. Oncotarget 8, 101784-101794. https://doi.org/10.18632/oncotarget.21695
  127. Zschiedrich, S., Budde, K. and Walz, G. (2015) Effect of everolimus on polycystic liver volume in autosomal dominant polycystic kidney disease. Clin. Exp. Nephrol. 19, 757-758. https://doi.org/10.1007/s10157-014-1059-x