Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, with an estimated prevalence between 1:1000 and 1:2500. It is mostly caused by mutations of the PKD1 and PKD2 genes encoding polycystin 1 (PC1) and polycystin 2 (PC2) that regulate cellular processes such as fluid transport, differentiation, proliferation, apoptosis and cell adhesion. Reduction of calcium ions and induction of cyclic adenosine monophosphate (sAMP) promote cyst enlargement by transepithelial fluid secretion and cell proliferation. Abnormal activation of MAPK/ERK pathway, dysregulated signaling of heterotrimeric G proteins, mTOR, phosphoinositide 3-kinase, AMPK, JAK/STAT activator of transcription and nuclear factor kB (NF-kB) are involved in cystogenesis. Another feature of cystic tissue is increased extracellular production and recruitment of inflammatory cells and abnormal connections among cells. Moreover, metabolic alterations in cystic cells including defective glucose metabolism, impaired beta-oxidation and abnormal mitochondrial activity were shown to be associated with cyst expansion. Although tolvaptan has been recently approved as a drug that slows ADPKD progression, some patients do not tolerate tolvaptan because of frequent aquaretic. The advances in the knowledge of multiple molecular pathways involved in cystogenesis led to the development of animal and cellular studies, followed by the development of several ongoing randomized controlled trials with promising drugs. Our review is aimed at pathophysiological mechanisms in cystogenesis in connection with the most promising drugs in animal and clinical studies.

Department of Nephrology 1st Faculty of Medicine Charles University General University Hospital Prague 128 08 Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University General University Hospital Prague 128 08 Prague Czech Republic

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Willey C.J., Blais J.D., Hall A.K., Krasa H.B., Makin A.J., Czerwiec F.S. Prevalence of autosomal dominant polycystic kidney disease in the European Union. Nephrol. Dial. Transplant. 2017;32:1356–1363. doi: 10.1093/ndt/gfw240. PubMed DOI PMC

Lanktree M.B., Haghighi A., Guiard E., Iliuta I.A., Song X., Harris P.C., Paterson A.D., Pei Y. Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing. J. Am. Soc. Nephrol. 2018;29:2593–2600. doi: 10.1681/ASN.2018050493. PubMed DOI PMC

Neumann H.P., Jilg C., Bacher J., Nabulsi Z., Malinoc A., Hummel B., Hoffmann M.M., Ortiz-Bruechle N., Glasker S., Pisarski P. Epidemiology of autosomal-dominant polycystic kidney disease: An in-depth clinical study for south-western Germany. Nephrol. Dial. Transplant. 2013;28:1472–1487. doi: 10.1093/ndt/gfs551. PubMed DOI

Spithoven E.M., Kramer A., Meijer E., Orskov B., Wanner C., Abad J.M., Aresté N., De La Torre R.A., Caskey F., Couchoud C., et al. Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: Prevalence and survival—An analysis of data from the ERA-EDTA Registry. Nephrol. Dial. Transplant. 2014;29:iv15–iv25. doi: 10.1093/ndt/gfu017. PubMed DOI PMC

Chapman A.B., Guay-Woodford L.M., Grantham J.J., Torres V.E., Bae K.T., Baumgarten D.A., Kenney P.J., King B.F., Glockner J.F., Wetzel L.H., et al. Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort1. Kidney Int. 2003;64:1035–1045. doi: 10.1046/j.1523-1755.2003.00185.x. PubMed DOI

Su Q., Hu F., Ge X., Lei J., Yu S., Wang T., Zhou Q., Mei C., Shi Y. Structure of the human PKD1-PKD2 complex. Science. 2018;80:eaat9819. doi: 10.1126/science.aat9819. PubMed DOI

Terryn S., Ho A., Beauwens R., Devuyst O. Fluid transport and cystogenesis in autosomal dominant polycystic kidney disease. Biochim. Biophys. Acta Mol. Basis Dis. 2011;1812:1314–1321. doi: 10.1016/j.bbadis.2011.01.011. PubMed DOI

Clark W.F., Devuyst O., Roussel R. The vasopressin system: New insights for patients with kidney diseases: Epidemiological evidence and therapeutic perspectives. J. Intern. Med. 2017;282:310–321. doi: 10.1111/joim.12654. PubMed DOI

Bastos A.P.A., Onuchic L. Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease. Braz. J. Med. Biol. Res. 2011;44:606–617. doi: 10.1590/S0100-879X2011007500068. PubMed DOI

Hanaoka K., Guggino W.B. cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells. J. Am. Soc. Nephrol. 2000;11:1179–1187. doi: 10.1681/ASN.V1171179. PubMed DOI

Bergmann C., Guay-Woodford L.M., Harris P.C., Horie S., Peters D.J.M., Torres V.E. Polycystic kidney disease. Nat. Rev. Dis. Primers. 2018;4:50. doi: 10.1038/s41572-018-0047-y. PubMed DOI PMC

Boletta A. Emerging evidence of a link between the polycystins and the mTOR pathways. Pathogenetics. 2009;2:6. doi: 10.1186/1755-8417-2-6. PubMed DOI PMC

Dere R., Wilson P.D., Sandford R.N., Walker C.L. Carboxy terminal tail of polycystin-1 regulates localization of TSC2 to repress mTOR. PLoS ONE. 2010;5:e9239. doi: 10.1371/journal.pone.0009239. PubMed DOI PMC

Saxton R.A., Sabatini D.M. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168:960–976. doi: 10.1016/j.cell.2017.02.004. PubMed DOI PMC

Li Y., Santoso N.G., Yu S., Woodward O.M., Qian F., Guggino W.B. Polycystin-1 interacts with inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling with implications for polycystic kidney disease. J. Biol. Chem. 2009;284:36431–36441. doi: 10.1074/jbc.M109.068916. PubMed DOI PMC

Santoso N.G., Cebotaru L., Guggino W.B. Polycystin-1,2, and STIM1 interact with IP 3 R to Modulate ER Ca2+ release through the PI3K/Akt pathway. Cell. Physiol. Biochem. 2011;27:715–726. doi: 10.1159/000330080. PubMed DOI PMC

Hemmings B.A., Restuccia D.F. PI3K-PKB/Akt Pathway. Cold Spring Harb. Perspect Biol. 2012;4:a011189. doi: 10.1101/cshperspect.a011189. PubMed DOI PMC

Boca M., Distefano G., Qian F., Bhunia A.K., Germino G.G., Boletta A. Polycystin-1 Induces Resistance to Apoptosis through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway. J. Am. Soc. Nephrol. 2006;17:637–647. doi: 10.1681/ASN.2005050534. PubMed DOI PMC

Bhunia A.K., Piontek K., Boletta A., Liu L., Qian F., Xu P.-N., Germino F., Germino G. PKD1 Induces p21waf1 and Regulation of the Cell Cycle via Direct Activation of the JAK-STAT Signaling Pathway in a Process Requiring PKD2. Cell. 2002;109:157–168. doi: 10.1016/S0092-8674(02)00716-X. PubMed DOI

Low S.H., Vasanth S., Larson C.H., Mukherjee S., Sharma N., Kinter M.T., Kane M.E., Obara T., Weimbs T. Polycystin-1, STAT6, and P100 Function in a Pathway that Transduces Ciliary Mechanosensation and is Activated in Polycystic Kidney Disease. Dev. Cell. 2006;10:57–69. doi: 10.1016/j.devcel.2005.12.005. PubMed DOI

Weimbs T., Olsan E.E., Talbot J.J. Regulation of STATs by polycystin-1 and their role in polycystic kidney disease. JAK STAT. 2013;2:e23650. doi: 10.4161/jkst.23650. PubMed DOI PMC

Li X., Luo Y., Starremans P.G., McNamara C.A., Pei Y., Zhou J. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat. Cell Biol. 2005;7:1202–1212. doi: 10.1038/ncb1326. PubMed DOI

Arnould T., Kim E., Tsiokas L., Jochimsen F., Grüning W., Chang J.D., Walz G. The Polycystic Kidney Disease 1 Gene Product Mediates Protein Kinase C α-dependent and c-Jun N-terminal Kinase-dependent Activation of the Transcription Factor AP-1. J. Biol. Chem. 1998;273:6013–6018. doi: 10.1074/jbc.273.11.6013. PubMed DOI

Arnould T., Sellin L., Benzing T., Tsiokas L., Cohen H.T., Kim E., Walz G. Cellular Activation Triggered by the Autosomal Dominant Polycystic Kidney Disease Gene Product PKD2. Mol. Cell. Biol. 1999;19:3423–3434. doi: 10.1128/MCB.19.5.3423. PubMed DOI PMC

Horsley V., Pavlath G.K. NFAT: Ubiquitous regulator of cell differentiation and adaptation. J. Cell Biol. 2002;156:771–774. doi: 10.1083/jcb.200111073. PubMed DOI PMC

Puri S., Magenheimer B.S., Maser R.L., Ryan E.M., Zien C.A., Walker D.D., Wallace D.P., Hempson S.J., Calvet J.P. Polycystin-1 Activates the Calcineurin/NFAT (Nuclear Factor of Activated T-cells) Signaling Pathway. J. Biol. Chem. 2004;279:55455–55464. doi: 10.1074/jbc.M402905200. PubMed DOI

Macián F., López-Rodríguez C., Rao A. Partners in transcription: NFAT and AP-1. Oncogene. 2001;20:2476–2489. doi: 10.1038/sj.onc.1204386. PubMed DOI

Steinhart Z., Angers S. Wnt signaling in development and tissue homeostasis. Development. 2018;145:dev146589. doi: 10.1242/dev.146589. PubMed DOI

Clevers H. Wnt/β-Catenin Signaling in Development and Disease. Cell. 2006;127:469–480. doi: 10.1016/j.cell.2006.10.018. PubMed DOI

Sugimura R., Li L. Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases. Birth Defects Res. Part C Embryo Today Rev. 2010;90:243–256. doi: 10.1002/bdrc.20195. PubMed DOI

Lancaster M.A., Gleeson J.G. Cystic kidney disease: The role of Wnt signaling. Trends Mol. Med. 2010;16:349–360. doi: 10.1016/j.molmed.2010.05.004. PubMed DOI PMC

Schrier R.W., Abebe K., Perrone R.D., Torres V.E., Braun W.E., Steinman T.I., Winklhofer F.T., Brosnahan G., Czarnecki P.G., Hogan M.C., et al. Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 2014;371:2255–2266. doi: 10.1056/NEJMoa1402685. PubMed DOI PMC

Torres V.E., Abebe K., Chapman A.B., Schrier R.W., Braun W.E., Steinman T.I., Winklhofer F.T., Brosnahan G., Czarnecki P.G., Hogan M.C., et al. Angiotensin Blockade in Late Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 2014;371:2267–2276. doi: 10.1056/NEJMoa1402686. PubMed DOI PMC

Torres V.E., Wang X., Qian Q., Somlo S., Harris P.C., Gattone V.H., 2nd Effective treatment of an orthologuous model of autosomal dominant polycystic kidney disease. Nat. Med. 2004;10:363–364. doi: 10.1038/nm1004. PubMed DOI

Wang X., Wu Y., Ward C.J., Harris P.C., Torres V.E. Vasopressin dierectly regulates cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 2008;19:102–108. doi: 10.1681/ASN.2007060688. PubMed DOI PMC

Torres V.E., Chapman A.B., Devuyst O., Gansevoort R.T., Grantham J.J., Higashihara E., Perrone R.D., Krasa H.B., Ouyang J., Czerwiec F.S., et al. Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 2012;367:2407–2418. doi: 10.1056/NEJMoa1205511. PubMed DOI PMC

Torres V.E., Chapman A.B., Devuyst O., Gansevoort R.T., Perrone R.D., Dandurand A., Ouyang J., Czerwiec F.S., Blais J.D., for the TEMPO 4:4 Trial Investigators Multicentric, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: The TEMPO 4:4 trial. Nephrol. Dial. Transplant. 2017;33:477–489. doi: 10.1093/ndt/gfx043. PubMed DOI PMC

Torres V.E., Chapman A.B., Devuyst O., Gansevoort R.T., Perrone R.D., Koch G., Ouyang J., McQuade R.D., Blais J.D., Czerwiec F.S., et al. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 2017;377:1930–1942. doi: 10.1056/NEJMoa1710030. PubMed DOI

Torres V.E., Gansevoort R.T., Perrone R.D., Chapman A.B., Ouyang J., Lee J., Japes H., Nourbakhsh A., Wang T. Tolvaptan in ADPKD Patients with Very Low Kidney Function. Kidney Int. Rep. 2021;6:2171–2178. doi: 10.1016/j.ekir.2021.05.037. PubMed DOI PMC

Chapman A.B., Bost J.E., Torres V.E., Guay-Woodford L., Bae K.T., Landsittel D., Li J., King B.F., Martin D., Wetzel L.H., et al. Kidney Volume and Functional Outcomes in Autosomal Dominant Polycystic Kidney Disease. Clin. J. Am. Soc. Nephrol. 2012;7:479–486. doi: 10.2215/CJN.09500911. PubMed DOI PMC

Cornec-Le Gall E., Audrezet M.-P., Rousseau A., Hourmant M., Renaudineau E., Charasse C., Morin M.-P., Moal M.-C., Dantal J., Wehbe B. The PROPKD score: A new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 2016;6:942–951. doi: 10.1681/ASN.2015010016. PubMed DOI PMC

Irazabal M.V., Blais J.D., Perrone R.D., Gansevoort R.T., Chapman A.B., Devuyst O., Higashihara E., Harris P.C., Zhou W., Ouyang J., et al. Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease: The TEMPO 3:4 Clinical Trial. Kidney Int. Rep. 2016;1:213–220. doi: 10.1016/j.ekir.2016.08.001. PubMed DOI PMC

Hogan M.C., Masyuk T.V., Page L.J., Kubly V.J., Bergstralh E.J., Li X., Kim B., King B.F., Glockner J., Holmes D.R., et al. Randomized Clinical Trial of Long-Acting Somatostatin for Autosomal Dominant Polycystic Kidney and Liver Disease. J. Am. Soc. Nephrol. 2010;21:1052–1061. doi: 10.1681/ASN.2009121291. PubMed DOI PMC

Ruggenenti P., Remuzzi A., Ondei P., Fasolini G., Antiga L., Ene-Iordache B., Remuzzi G., Epstein F.H. Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int. 2005;68:206–216. doi: 10.1111/j.1523-1755.2005.00395.x. PubMed DOI

Caroli A., Perico N., Perna A., Antiga L., Brambilla P., Pisani A., Visciano B., Imbriaco M., Messa P., Cerutti R., et al. Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): A randomized placebo-controlled, multicentre trial. Lancet. 2013;382:1485–1495. doi: 10.1016/S0140-6736(13)61407-5. PubMed DOI

Meijer E., Drenth J.P., d’Agnolo H., Casteleijn N.F., de Fijter J.W., Gevers T.J., Kappert P., Peters D.J., Salih M., Soonawala D., et al. Rationale and design of the DIPAK 1 study: A randomized controlled clinical trial assessing the efficacy of lanreotide to Halt disease progression in autosomal dominant polycystic kidney disease. Am. J. Kidney Dis. 2014;63:446–455. doi: 10.1053/j.ajkd.2013.10.011. PubMed DOI PMC

van Keimpema L., Nevens F., Vanslembrouck R., van Oijen M.G., Hoffmann A.L., Dekker H.M., de Man R.A., Drenth J.P. Lanreotide reduces volume of polycystic liver: A randomized, double-blind, placebo-controlled trial. Gastroenterology. 2009;137:1661–1668. doi: 10.1053/j.gastro.2009.07.052. PubMed DOI

Chrispijn M., Nevens F., Gevers T.J.G., Vanslembrouck R., van Oijen M.G.H., Coudyzer W., Hoffmann A.L., Dekker H.M., de Man R.A., van Keimpema L., et al. The long-term outcome of patients with polycystic liver disease treated with lanreotide. Aliment. Pharmacol. Ther. 2012;35:266–274. doi: 10.1111/j.1365-2036.2011.04923.x. PubMed DOI

Wang X., Constans M.M., Chebib F.T., Torres V.E., Pellegrini L. Effect of a vasopressin V2 receptor antagonist on polycystic kidney disease development in a rat model. Am. J. Nephrol. 2019;49:487–493. doi: 10.1159/000500667. PubMed DOI PMC

Woodhead J.L., Pellegrini L., Shoda L.K.M., Howell B.A. Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney Disease Using Quantitative Systems Toxicology Modeling. Pharm. Res. 2020;37:24. doi: 10.1007/s11095-019-2726-0. PubMed DOI PMC

Xu N., Glockner J.F., Rossetti S., Babovich-Vuksanovic D., Harris P.C., Torres V.E. Autosomal dominant polycystic kidney disease coexisting with cystic fibrosis. J. Nephrol. 2006;19:529–534. PubMed

Yanda M.K., Liu Q., Cebotaru L. A potential strategy for reducing cysts in autosomal dominant polycystic kidney disease with a CFTR corrector. J. Biol. Chem. 2018;293:11513–11526. doi: 10.1074/jbc.RA118.001846. PubMed DOI PMC

Yuajit C., Homvisasevongsa S., Chatsudthipong L., Soodvilai S., Muanprasat C., Chatsudthipong V. Steviol Reduces MDCK Cyst Formation and Growth by Inhibiting CFTR Channel Activity and Promoting Proteasome-Mediated CFTR Degradation. PLoS ONE. 2013;8:e58871. doi: 10.1371/journal.pone.0058871. PubMed DOI PMC

Nantavishit J., Chatsudthipong V., Soodvilai S. Lansoprazole reduces renal cyst in polycystic kidney disease via inhibition of cell proliferation and fluid secretion. Biochem. Pharmacol. 2018;154:175–182. doi: 10.1016/j.bcp.2018.05.005. PubMed DOI

Albaqumi M., Srivastava S., Li Z., Zhdnova O., Wulff H., Itani O., Wallace D.P., Skolnik E.Y. KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal dominant polycystic kidney disease. Kidney Int. 2008;74:740–749. doi: 10.1038/ki.2008.246. PubMed DOI

Cabrita I., Kraus A., Scholz J.K., Skoczynski K., Schreiber R., Kunzelmann K., Buchholz B. Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo. Nat. Commun. 2020;11:4320. doi: 10.1038/s41467-020-18104-5. PubMed DOI PMC

Miner K., Labitzke K., Liu B., Wang P., Henckels K., Gaida K., Elliott R., Chen J.J., Liu L., Leith A., et al. Drug repurposing: The anthelmintics niclosamide and nitazoxanide are potent TMEM16A antagonists that fully bronchodilate airways. Front. Pharmacol. 2019;14 doi: 10.3389/fphar.2019.00051. PubMed DOI PMC

Seo Y., Kim J., Chang J., Kim S.S., Namkung W., Kim I. Synthesis and biological evaluation of novel Ani9 derivatives as potent and selective ANO1 inhibitors. Eur. J. Med. Chem. 2018;160:245–255. doi: 10.1016/j.ejmech.2018.10.002. PubMed DOI

Elliot J., Zheleznova N.N., Wilson P.D. c-Src inactivation reduces renal peithelial cell-matrix adhesion, proliferation, and cyst formation. Am. J. Physiol. Cell Physiol. 2011;302:C522–C529. doi: 10.1152/ajpcell.00163.2010. PubMed DOI PMC

Tesar V., Ciechanowski K., Pei Y., Barash I., Shannon M., Li R., Williams J.H., Levisetti M., Arkin S., Serra A. Bosutinib versus Placebo for Autosomal Dominant Polycystic Kidney Disease. J. Am. Soc. Nephrol. 2017;28:3404–3413. doi: 10.1681/ASN.2016111232. PubMed DOI PMC

Sweeney W.E., Frost P., Avner E.D. Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease. World J. Nephrol. 2017;6:188–200. doi: 10.5527/wjn.v6.i4.188. PubMed DOI PMC

Kawai T., Masaki T., Doi S., Arakawa T., Yokoyama Y., Doi T., Kohno N., Yorioka N. PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta. Lab. Investig. 2009;89:47–58. doi: 10.1038/labinvest.2008.104. PubMed DOI

Nofziger C., Brown K.K., Smith C.D., Harrington W., Murray D., Bisi J., Ashton T.T., Maurio F.P., Kalsi K., West T.A., et al. PPARgamma agonists inhibit vasopressin-mediated anion transport in the MDCK-C7 cell line. Am. J. Physiol. Renal. Physiol. 2009;297:F55–F62. doi: 10.1152/ajprenal.00090.2009. PubMed DOI

Kanhai A.A., Bange H., Verburg L., Dijkstra K.L., Price L.S., Peters D.J.M., Leonhard W.N. Renal cyst growth is attenuated by a combination of tolvaptan and pioglitazon, while pioglitazone treatment alone is not effective. Sci. Rep. 2020;10:1672. doi: 10.1038/s41598-020-58382-z. PubMed DOI PMC

Takiar V., Nishio S., Seo-Mayer P., King J.D., Jr., Li H., Zhang L., Karihaloo A., Hallows K.R., Somlo S., Caplan M.J. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc. Natl. Acad. Sci. USA. 2011;108:2462–2467. doi: 10.1073/pnas.1011498108. PubMed DOI PMC

Menezes L.F., Lin C.-C., Zhou F., Germino G.G. Fatty Acid Oxidation is Impaired in An Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease. eBioMedicine. 2016;5:183–192. doi: 10.1016/j.ebiom.2016.01.027. PubMed DOI PMC

Chang M.-Y., Ma T.-L., Hung C.-C., Tian Y.-C., Chen Y.-C., Ming-Yang C., Cheng Y.-C. Metformin Inhibits Cyst Formation in a Zebrafish Model of Polycystin-2 Deficiency. Sci. Rep. 2017;7:7161. doi: 10.1038/s41598-017-07300-x. PubMed DOI PMC

Perrone R.D., Abebe K.Z., Watnick T.J., Althouse A.D., Hallows K.R., Lalama C.M., Miskulin D.C., Seliger S.L., Tao C., Harris P.C., et al. Primary results of the randomized trial of metformin administration in polycystic kideny disease (TAME PKD) Kidney Int. 2021;100:684–696. doi: 10.1016/j.kint.2021.06.013. PubMed DOI PMC

Fassett R.G., Coombes J.S., Packham D., Fairley K.F., Kincaid-Smith P. Effect of pravastatin on kidney function and urinary protein excretion in autosomal dominant polycystic kidney disease. Scand. J. Urol. Nephrol. 2009;44:56–61. doi: 10.3109/00365590903359908. PubMed DOI

Cadnapaphornchai M.A., George D.M., McFann K., Wang W., Gitomer B., Strain J.D., Schrier R.W. Effect of pravastatin on total kidney volume, left ventricular mass index, and microalbuminuria in pediatric autosomal dominant polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 2014;9:889–896. doi: 10.2215/CJN.08350813. PubMed DOI PMC

Brosnahan G.M., Abebe K.Z., Rahbari-Oskoui F.F., Patterson C.G., Bae K.T., Schrier R.W., Braun W.E., Chapman A.B., Flessner M.F., Harris P.C., et al. Effect of statin therapy on the progression of autosomal dominant polycystic kidney disease, a secondary analysis of the HALT PKD Trials. Curr. Hypertens. Rev. 2017;13:109–120. doi: 10.2174/1573402113666170427142815. PubMed DOI PMC

Yamaguchi T., Pelling J.C., Ramaswamy N.T., Eppler J.W., Wallace D.P., Nagao S., Rome L.A., Sullivan L.P., Grantham J.J. cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracelllular signal-regulated kinase pathway. Kidney Int. 2000;57:1460–1471. doi: 10.1046/j.1523-1755.2000.00991.x. PubMed DOI

Buchholz B., Klanke B., Schley G., Bollag G., Tsai J., Kroening S., Yoshihara D., Wallace D.P., Kraenzlin B., Gretz N., et al. The Raf kinase inhibitor PLX5568 slows cyst proliferation in rat polycystic kidney disease but promotes renal and hepatic fibrosis. Nephrol. Dial. Transplant. 2011;26:3458–3465. doi: 10.1093/ndt/gfr432. PubMed DOI PMC

Podrini C., Cassina L., Boletta A. Metabolic reprogramming and the role of mitochondria in polycystic kidney disease. Cell. Signal. 2019;67:109495. doi: 10.1016/j.cellsig.2019.109495. PubMed DOI

Rowe I., Chiaravalli M., Mannella V., Ulisse V., Quilici G., Pema M., Song X.W., Xu H., Mari S., Qian F., et al. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat. Med. 2013;19:488–493. doi: 10.1038/nm.3092. PubMed DOI PMC

Kipp K.R., Rezaei M., Lin L., Dewey E.C., Weimbs T. A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease. Am. J. Physiol. Renal Physiol. 2016;310:F726–F731. doi: 10.1152/ajprenal.00551.2015. PubMed DOI PMC

Warner G., Hein K.Z., Nin V., Edwards M., Chini C.C., Hopp K., Harris P.C., Torres V.E., Chini E.N. Food Restriction Ameliorates the Development of Polycystic Kidney Disease. J. Am. Soc. Nephrol. 2015;27:1437–1447. doi: 10.1681/ASN.2015020132. PubMed DOI PMC

Nowak K.L., You Z., Gitomer B., Brosnahan G., Torres V.E., Chapman A.B., Perrone R.D., Steinman T.I., Abebe K.Z., Rahbari-Oskoui F.F., et al. Overweight and obesity are predictors of progression in early autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 2018;29:571–578. doi: 10.1681/ASN.2017070819. PubMed DOI PMC

Torres V.E., Abebe K.Z., Schrier R.W., Perrone R.D., Chapman A.B., Yu A.S., Braun W.E., Steinman T.I., Brosnahan G., Hogan M.C., et al. Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease. Kidney Int. 2017;91:493–500. doi: 10.1016/j.kint.2016.10.018. PubMed DOI PMC

Riwanto M., Kapoor S., Rodriguez D., Edenhofer I., Segerer S., Wüthrich R.P. Inhibition of Aerobic Glycolysis Attenuates Disease Progression in Polycystic Kidney Disease. PLoS ONE. 2016;11:e0146654. doi: 10.1371/journal.pone.0146654. PubMed DOI PMC

Walz G., Budde K., Mannaa M., Nürnberger J., Wanner C., Sommerer C., Kunzendorf U., Banas B., Hörl W.H., Obermüller N., et al. Everolimus in Patients with Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 2010;363:830–840. doi: 10.1056/NEJMoa1003491. PubMed DOI

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. doi: 10.1056/NEJMoa0907419. PubMed DOI

Pergola P.E., Raskin P., Toto R.D., Meyer C.J., Huff J.W., Grossman E.B., Krauth M., Ruiz S., Audhya P., Christ-Schmidt H., et al. Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes. N. Engl. J. Med. 2011;365:327–336. doi: 10.1056/NEJMoa1105351. PubMed DOI

de Zeeuw D., Akizawa T., Audhya P., Bakris G.L., Chin M., Christ-Schmidt H., Goldsberry A., Houser M., Krauth M., Lambers Heerspink H.J., et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med. 2013;329:2492–2503. doi: 10.1056/NEJMoa1306033. PubMed DOI PMC

Lu Y., Sun Y., Liu Z., Lu Y., Zhu X., Lan B., Mi Z., Dang L., Li N., Zhan W., et al. Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease. Sci. Transl. Med. 2020;12:eaba3613. doi: 10.1126/scitranslmed.aba3613. PubMed DOI

Gattone V.H., Chen N.X., Sinders R.M., Seifert M.F., Duan D., Martin D., Henley C., Moe S.M. Calcimimetic Inhibits Late-Stage Cyst Growth in ADPKD. J. Am. Soc. Nephrol. 2009;20:1527–1532. doi: 10.1681/ASN.2008090927. PubMed DOI PMC

Di Mise A., Wang X., Ye H., Pellegrini L., Torres V.E., Valenti G. Pre-clinical evaluation of dual targeting of the GPCRs CaSR and V2R as therapeutic strategy for autosomal dominant polycystic kidney disease. FASEB J. 2021;35:e21874. doi: 10.1096/fj.202100774R. PubMed DOI PMC

He S., Chen M., Lin X., Lv Z., Liang R., Huang L. Triptolide inhibits PDGF-induced proliferation of ASMCs therough G0/G1 cell cycle arrest and suppression of the AKT/NK-κB/cyclinD1 signaling pathway. Eur. J. Pharmacol. 2020;867:e172811. doi: 10.1016/j.ejphar.2019.172811. PubMed DOI

Chen D., Ma Y., Wang X., Yu S., Li L., Dai B., Mao Z., Liu H., Liu S., Mei C. Triptolide-Containing Formulation in Patients With Autosomal Dominant Polycystic Kidney Disease and Proteinuria: An Uncontrolled Trial. Am. J. Kidney Dis. 2014;63:1070–1072. doi: 10.1053/j.ajkd.2014.01.418. PubMed DOI

Bukanov N.O., Moreno S.E., Natoli T.A., Rogers K.A., Smith L.A., Ledbetter S.R., Oumata N., Galons H., Meijer L., Ibraghimov-Beskrovnaya O. CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD. Cell Cycle. 2012;11:4040–4046. doi: 10.4161/cc.22375. PubMed DOI PMC

Cebotaru L., Liu Q., Yanda M.K., Boinot C., Outeda P., Huso D.L., Watnick T., Guggino W.B., Cebotaru V. Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease. Kidney Int. 2016;90:90–99. doi: 10.1016/j.kint.2016.01.026. PubMed DOI PMC

Cao Y., Semanchik N., Lee S.H., Somlo S., Barbano P.E., Coifman R., Sun Z. Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models. Proc. Natl. Acad. Sci. USA. 2009;106:21819–21824. doi: 10.1073/pnas.0911987106. PubMed DOI PMC

Natoli T.A., Modur V., Ibraghimov-Beskrovnaya O. Glycosphingolipid metabolism and polycystic kidney disease. Cell. Signal. 2020;69:109526. doi: 10.1016/j.cellsig.2020.109526. PubMed DOI

Natoli T.A., Smith L.A., Rogers K.A., Wang B., Komarnitsky S., Budman Y., Belenky A., Bukanov N.O., Dackowski W.R., Husson H., et al. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat. Med. 2010;16:788–792. doi: 10.1038/nm.2171. PubMed DOI PMC

Zoja C., Corna D., Locatelli M., Rottoli D., Pezzotta A., Morigi M., Zanchi C., Buelli S., Guglielmotti A., Perico N., et al. Effects of MCP-1 Inhibition by Bindarit Therapy in a Rat Model of Polycystic Kidney Disease. Nephron. 2014;129:52–61. doi: 10.1159/000369149. PubMed DOI

Li X., Magenheimer B.S., Xia S., Johnson T., Wallace D.P., Calvet J.P., Li R. A tumor necrosis factor-α–mediated pathway promoting autosomal dominant polycystic kidney disease. Nat. Med. 2008;14:863–868. doi: 10.1038/nm1783. PubMed DOI PMC

Cordido A., Nuñez-Gonzalez L., Martinez-Moreno J.M., Lamas-Gonzalez O., Rodriguez-Osorio L., Perez-Gomez M.V., Martin-Sanchez D., Outeda P., Chiaravalli M., Watnick T., et al. TWEAK signaling pathway blockade slows cyst growth and disease progression in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 2021;32:1913–1932. doi: 10.1681/ASN.2020071094. PubMed DOI PMC

Patel V., Williams D., Hajarnis S., Hunter R., Pontoglio M., Somlo S., Igarashi P. miR-17 92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease. Proc. Natl. Acad. Sci. USA. 2013;110:10765–10770. doi: 10.1073/pnas.1301693110. PubMed DOI PMC

Lee E.C., Valencia T., Allerson C., Schairer A., Flaten A., Yheskel M., Kersjes K., Li J., Gatto S., Takhar M., et al. Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 fot the treatment of polycystic kidney disease. Nat. Commun. 2019;10:4148. doi: 10.1038/s41467-019-11918-y. PubMed DOI PMC

Kim D.Y., Woo Y.M., Lee S., Oh S., Shin Y., Shin J.-O., Park E.Y., Ko J.Y., Lee E.J., Bok J., et al. Impact of miR-192 and miR-194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease. FASEB J. 2018;33:2870–2884. doi: 10.1096/fj.201800563RR. PubMed DOI