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Role of apoptosis in the development of autosomal dominant polycystic kidney disease (ADPKD)

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disorder in the Western world and is characterized by cystogenesis that often leads to end-stage renal disease (ESRD). Mutations in the pkd1 gene, encoding for polycystin-1 (PC1) and its interaction partner pkd2, encoding for polycystin-2 (PC2), are the main drivers of this disease. PC1 and PC2 form a multiprotein membrane complex at cilia sites of the plasma membrane and at intracellular membranes. This complex mediates calcium influx and stimulates various signaling pathways regulating cell survival, proliferation and differentiation. The molecular consequences of pkd1 and pkd2 mutations are still a matter of debate. In particular, the ways in which the cysts are initially formed and progress throughout the disease are unknown. The mechanisms proposed to play a role include enhanced cell proliferation, increased apoptotic cell death and diminished autophagy. In this review, we summarize our current understanding about the contribution of apoptosis to cystogenesis and ADPKD. We present the animal models and the tools and methods that have been created to analyze this process. We also critically review the data that are in favor or against the involvement of apoptosis in disease generation. We argue that apoptosis is probably not the sole driver of cystogenesis but that a cooperative action of cell death, compensatory cell proliferation and perturbed autophagy gradually establish the disease. Finally, we propose novel strategies for uncovering the mode of action of PC1 and PC2 and suggest means by which their dysfunction or loss of expression lead to cystogenesis and ADPKD development.

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References

  • Aglietti R, Dueber E (2017) Recent insights into the molecular mechanisms underlying pyroptosis and gasdermin family functions. Trends Immunol 38:261–271

    Article  CAS  PubMed  Google Scholar 

  • Arnould T, Kim E, Tsiokas L, Jochimsen F, Gruning W, Chang JD, Walz G (1998) The polycystic kidney disease 1 gene product mediates protein kinase C alpha-dependent and c-Jun N-terminal kinase-dependent activation of the transcription factor AP-1. J Biol Chem 273:6013–6018

    Article  CAS  PubMed  Google Scholar 

  • Bai D, Ueno L, Vogt PK (2009) Akt-mediated regulation of NFκB and the essentialness of NFκB for the oncogenicity of PI3K and Akt. Int J Cancer 125:2863–2870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bassik MC, Scorrano L, Oakes SA, Pozzan T, Korsmeyer SJ (2004) Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis. EMBO J 23:1207–1216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Battini L, Fedorova E, Macip S, Li X, Wilson PD, Gusella GL (2006) Stable knockdown of polycystin-1 confers integrin-alpha2beta1-mediated anoikis resistance. J Am Soc Nephrol 17:3049–3058

    Article  CAS  PubMed  Google Scholar 

  • Battini L, Macip S, Fedorova E, Dikman S, Somlo S, Montagna C, Gusella GL (2008) Loss of polycystin-1 causes centrosome amplification and genomic instability. Hum Mol Genet 17:2819–2833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berry DL, Baehrecke EH (2007) Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 131:1137–1148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhola PD, Letai A (2016) Mitochondria—judges and executioners of cell death sentences. Mol Cell 61:695–704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhunia AK, Piontek K, Boletta A, Liu L, Qian F, Xu P-N, Germino FJ, Germino GG (2002) PKD1 induces p21waf1 and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell 109:157–168

    Article  CAS  PubMed  Google Scholar 

  • Bisceglia M, Galliani CA, Senger C, Stallone C, Sessa A (2006) Renal cystic diseases: a review. Adv Anat Pathol 13:26–56

    Article  PubMed  Google Scholar 

  • Boca M, Distefano G, Qian F, Bhunia AK, Germino GG, Boletta A (2006) Polycystin-1 induces resistance to apoptosis through the phosphatidylinositol 3-kinase/Akt signaling pathway. J Am Soc Nephrol 17:637–647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boca M, D’Amato L, Distefano G, Polishchuk RS, Germino GG, Boletta A (2007) Polycystin-1 induces cell migration by regulating PI3kinase-dependent cytoskeletal rearrangements and GSK3-β dependent cell cell mechanical adhesion. Mol Biol Cell 18:4050–4061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boletta A, Qian F, Onuchic LF, Bhunia AK, Phakdeekitcharoen B, Hanaoka K, Guggino W, Monaco L, Germino GG (2000) Polycystin-1, the gene product of PKD1, induces resistance to apoptosis and spontaneous tubulogenesis in MDCK cells. Mol Cell 6:1267–1273

    Article  CAS  PubMed  Google Scholar 

  • Borner C (1996) Diminished cell proliferation associated with the death-protective activity of Bcl-2. J Biol Chem 271:12695–12698

    CAS  PubMed  Google Scholar 

  • Bouchier-Hayes L, Muñoz-Pinedo C, Connell S, Green DR (2008) Measuring apoptosis at the single cell level. Methods 44:222–228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bouillet P, Cory S, Zhang L-C, Strasser A, Adams JM (2001) Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim. Dev Cell 1:645–653

    Article  CAS  PubMed  Google Scholar 

  • Boulter C, Mulroy S, Webb S, Fleming S, Brindle K, Sandford R (2001) Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene. Proc Natl Acad Sci 98:12174–12179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brady SC, Allan LA, Clarke PR (2005) Regulation of caspase 9 through phosphorylation by protein kinase C zeta in response to hyperosmotic stress. Mol Cell Biol 25:10543–10555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Braun F, Bertin-Ciftci J, Gallouet A-S, Millour J, Juin P (2011) Serum-nutrient starvation induces cell death mediated by Bax and Puma that is counteracted by p21 and unmasked by Bcl-xL inhibition. PLoS One 6:e23577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bukanov NO, Smith LA, Klinger KW, Ledbetter SR, Ibraghimov-Beskrovnaya O (2006) Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature 444:949–952

    Article  CAS  PubMed  Google Scholar 

  • Cai Y, Maeda Y, Cedzich A, Torres VE, Wu G, Hayashi T, Mochizuki T, Park JH, Witzgall R, Somlo S (1999) Identification and characterization of polycystin-2, the PKD2 gene product. J Biol Chem 274:28557–28565

    Article  CAS  PubMed  Google Scholar 

  • Cai Y, Fedeles SV, Dong K, Anyatonwu G, Onoe T, Mitobe M, Gao J-D, Okuhara D, Tian X, Gallagher A-R, Tang Z, Xie X, Lalioti MD, Lee A-H, Ehrlich BE, Somlo S (2014) Altered trafficking and stability of polycystins underlie polycystic kidney disease. J Clin Invest 124:5129–5144

    Article  PubMed  PubMed Central  Google Scholar 

  • Castedo M, Perfettini J-L, Roumier T, Andreau K, Medema R, Kroemer G (2004) Cell death by mitotic catastrophe: a molecular definition. Oncogene 23:2825–2837

    Article  CAS  PubMed  Google Scholar 

  • Chapin HC, Caplan MJ (2010) The cell biology of polycystic kidney disease. J Cell Biol 191:701–710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charvet C, Wissler M, Brauns-Schubert P, Wang SJ, Tang Y, Sigloch FC, Mellert H, Brandenburg M, Lindner SE, Breit B, Green DR, McMahon SB, Borner C, Gu W, Maurer U (2011) Phosphorylation of Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53. Mol Cell 42:584–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chauvet V, Qian F, Boute N, Cai Y, Phakdeekitacharoen B, Onuchic LF, Attié-Bitach T, Guicharnaud L, Devuyst O, Germino GG, Gubler M-C (2002) Expression of PKD1 and PKD2 transcripts and proteins in human embryo and during normal kidney development. Am J Pathol 160:973–983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X-Z, Li Q, Wu Y, Liang G, Lara CJ, Cantiello HF (2008) Submembraneous microtubule cytoskeleton: interaction of TRPP2 with the cell cytoskeleton. FEBS J 275:4675–4683

    Article  CAS  PubMed  Google Scholar 

  • Chiarugi P, Giannoni E (2008) Anoikis: a necessary death program for anchorage-dependent cells. Biochem Pharmacol 76:1352–1364

    Article  CAS  PubMed  Google Scholar 

  • Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR (2010) The BCL-2 family reunion. Mol Cell 37:299–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christensen ME, Jansen ES, Sanchez W, Waterhouse NJ (2013) Flow cytometry based assays for the measurement of apoptosis-associated mitochondrial membrane depolarisation and cytochrome c release. Methods 61:138–145

    Article  CAS  PubMed  Google Scholar 

  • Couillard M, Guillaume R, Tanji N, D’Agati V, Trudel M (2002) C-myc-induced apoptosis in polycystic kidney disease is independent of FasL/Fas interaction. Cancer Res 62:2210–2214

    CAS  PubMed  Google Scholar 

  • Cubillos-Ruiz JR, Bettigole SE, Glimcher LH (2017) Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer. Cell 168:692–706

    Article  CAS  PubMed  Google Scholar 

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241

    Article  CAS  PubMed  Google Scholar 

  • Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112–119

    Article  CAS  PubMed  Google Scholar 

  • Delling M, Indzhykulian AA, Liu X, Li Y, Xie T, Corey DP, Clapham DE (2016) Primary cilia are not calcium-responsive mechanosensors. Nature 531:656–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dewson G (2015) Two roads to death—Bax targets mitochondria by distinct routes before or during apoptotic cell death. Mol Cell Oncol 2:e974460

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dewson G, Kratina T, Sim HW, Puthalakath H, Adams JM, Colman PM, Kluck RM (2008) To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3:groove interactions. Mol Cell 30:369–380

    Article  CAS  PubMed  Google Scholar 

  • Dickens LS, Powley IR, Hughes MA, MacFarlane M (2012) The “complexities” of life and death: death receptor signalling platforms. Exp Cell Res 318:1269–1277

    Article  CAS  PubMed  Google Scholar 

  • Dillon CP, Tummers B, Baran K, Green DR (2016) Developmental checkpoints guarded by regulated necrosis. Cell Mol Life Sci 73:2125–2136

    Article  CAS  PubMed  Google Scholar 

  • Distefano G, Boca M, Rowe I, Wodarczyk C, Ma L, Piontek KB, Germino GG, Pandolfi PP, Boletta A (2009) Polycystin-1 regulates extracellular signal-regulated kinase-dependent phosphorylation of Tuberin to control cell size through mTOR and its downstream effectors S6K and 4EBP1. Mol Cell Biol 29:2359–2371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C, Patel D, Bauer A, Cantley A, Yang W, Morrison B, Stockwell B (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ecder T, Melnikov VY, Stanley M, Korular D, Lucia MS, Schrier RW, Edelstein CL (2002) Caspases, Bcl-2 proteins and apoptosis in autosomal-dominant polycystic kidney disease. Kidney Int 61:1220–1230

    Article  CAS  PubMed  Google Scholar 

  • Edelstein CL (2005) What is the role of tubular epithelial cell apoptosis in polycystic kidney disease (PKD)? Cell Cycle 4:1550–1554

    Article  CAS  PubMed  Google Scholar 

  • Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC (1992) Induction of apoptosis in fibroblasts by c-myc protein. Cell 69:119–128

    Article  CAS  PubMed  Google Scholar 

  • Fan LX, Zhou X, Sweeney WE Jr, Wallace DP, Avner ED, Grantham JJ, Li X (2013) Smac-mimetic-induced epithelial cell death reduces the growth of renal cysts. J Am Soc Nephrol 24:2010–2022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Favaloro B, Allocati N, Graziano V, Di Ilio C, De Laurenzi V (2012) Role of apoptosis in disease. Aging (Albany NY) 4:330–349

    Article  CAS  Google Scholar 

  • Fedeles SV, So JS, Shrikhande A, Lee SH, Gallagher AR, Barkauskas CE, Somlo S, Lee AH (2015) Sec63 and Xbp1 regulate IRE1alpha activity and polycystic disease severity. J Clin Invest 125:1955–1967

    Article  PubMed  PubMed Central  Google Scholar 

  • Fedorov LM, Schmittwolf C, Amann K, Thomas WH, Muller AM, Schubert H, Domen J, Kneitz B (2006) Renal failure causes early death of bcl-2 deficient mice. Mech Ageing Dev 127:600–609

    Article  CAS  PubMed  Google Scholar 

  • Foyouzi-Youssefi R, Arnaudeau S, Borner C, Kelley WL, Tschopp J, Lew DP, Demaurex N, Krause K-H (2000) Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum. Proc Natl Acad Sci U S A 97:5723–5728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fulda S (2015) Promises and challenges of Smac mimetics as cancer therapeutics. Clin Cancer Res 21:5030–5036

    Article  CAS  PubMed  Google Scholar 

  • Gautam S, Kirschnek S, Wiesmeier M, Vier J, Häcker G (2014) Roscovitine-induced apoptosis in neutrophils and neutrophil progenitors is regulated by the Bcl-2-family members Bim, Puma, Noxa and mcl-1. PLoS One 8:e79352

    Article  CAS  Google Scholar 

  • Geissler A, Haun F, Frank DO, Wieland K, Simon MM, Idzko M, Davis RJ, Maurer U, Borner C (2013) Apoptosis induced by the fungal pathogen gliotoxin requires a triple phosphorylation of Bim by JNK. Cell Death Differ 20:1317–1329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glab JA, Mbogo GW, Puthalakath H (2017) BH3-only proteins in health and disease. Int Rev Cell Mol Biol 328:163–196

    Article  CAS  PubMed  Google Scholar 

  • Goilav B (2011) Apoptosis in polycystic kidney disease. Biochim Biophys Acta 1812:1272–1280

    Article  CAS  PubMed  Google Scholar 

  • Guay-Woodford LM (2003) Murine models of polycystic kidney disease: molecular and therapeutic insights. Am J Physiol Renal Physiol 285:F1034–F1049

    Article  CAS  PubMed  Google Scholar 

  • Happe H, Peters DJM (2014) Translational research in ADPKD: lessons from animal models. Nat Rev Nephrol 10:587–601

    Article  CAS  PubMed  Google Scholar 

  • Harris PC, Torres VE (2009) Polycystic kidney disease. Annu Rev Med 60:321–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haschka MD, Soratroi C, Kirschnek S, Hacker G, Hilbe R, Geley S, Villunger A, Fava LL (2015) The NOXA-MCL1-BIM axis defines lifespan on extended mitotic arrest. Nat Commun 6:6891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hopp K, Ward CJ, Hommerding CJ, Nasr SH, Tuan HF, Gainullin VG, Rossetti S, Torres VE, Harris PC (2012) Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J Clin Invest 122:4257–4273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu B, He X, Li A, Qiu Q, Li C, Liang D, Zhao P, Ma J, Coffey RJ, Zhan Q, Wu G (2011) Cystogenesis in ARPKD results from increased apoptosis in collecting duct epithelial cells of Pkhd1 mutant kidneys. Exp Cell Res 317:173–187

    Article  CAS  PubMed  Google Scholar 

  • Hughes P, Robati M, Lu W, Zhou J, Strasser A, Bouillet P (2006) Loss of PKD1 and loss of Bcl-2 elicit polycystic kidney disease through distinct mechanisms. Cell Death Differ 13:1123–1127

    Article  CAS  PubMed  Google Scholar 

  • Iurlaro R, Muñoz-Pinedo C (2016) Cell death induced by endoplasmic reticulum stress. FEBS J 283:2640–2652

    Article  CAS  PubMed  Google Scholar 

  • Jiang L, Kon N, Li T, Wang S-J, Su T, Hibshoosh H, Baer R, Gu W (2015) Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520:57–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson SC, Rabinovitch PS, Kaeberlein M (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493:338–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kathem SH, Mohieldin AM, Nauli SM (2014) The roles of primary cilia in polycystic kidney disease. AIMS Mol Sci 1:27–46

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim E, Arnould T, Sellin LK, Benzing T, Fan MJ, Grüning W, Sokol SY, Drummond I, Walz G (1999) The polycystic kidney disease 1 gene product modulates Wnt signaling. J Biol Chem 274:4947–4953

    Article  CAS  PubMed  Google Scholar 

  • Komatsu M, Waguri S, Chiba T, Murata S, J-i I, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884

    Article  CAS  PubMed  Google Scholar 

  • Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, Chanrion M, Kelly GL, Gong J-N, Moujalled DM, Bruno A, Csekei M, Paczal A, Szabo ZB, Sipos S, Radics G, Proszenyak A, Balint B, Ondi L, Blasko G, Robertson A, Surgenor A, Dokurno P, Chen I, Matassova N, Smith J, Pedder C, Graham C, Studeny A, Lysiak-Auvity G, Girard AM, Gravé F, Segal D, Riffkin CD, Pomilio G, Galbraith LC, Aubrey BJ, Brennan MS, Herold MJ, Chang C, Guasconi G, Cauquil N, Melchiore F, Guigal-Stephan N, Lockhart B, Colland F, Hickman JA, Roberts AW, Huang DC, Wei AH, Strasser A, Lessene G, Geneste O (2016) The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 538:477–482

    Article  PubMed  CAS  Google Scholar 

  • Koulen P, Cai Y, Geng L, Maeda Y, Nishimura S, Witzgall R, Ehrlich BE, Somlo S (2002) Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol 4:191–197

    Article  CAS  PubMed  Google Scholar 

  • La Rovere RML, Roest G, Bultynck G, Parys JB (2016) Intracellular Ca2+ signaling and Ca2+ microdomains in the control of cell survival, apoptosis and autophagy. Cell Calcium 60:74–87

    Article  CAS  PubMed  Google Scholar 

  • Lal M, Song X, Pluznick JL, Di Giovanni V, Merrick DM, Rosenblum ND, Chauvet V, Gottardi CJ, Pei Y, Caplan MJ (2008) Polycystin-1 C-terminal tail associates with β-catenin and inhibits canonical Wnt signaling. Hum Mol Genet 17:3105–3117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lantinga-van Leeuwen IS, Dauwerse JG, Baelde HJ, Leonhard WN, van de Wal A, Ward CJ, Verbeek S, Deruiter MC, Breuning MH, de Heer E, Peters DJ (2004) Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum Mol Genet 13:3069–3077

    Article  CAS  PubMed  Google Scholar 

  • Lee K, Boctor S, LMC B, Gusella GL (2015a) Inactivation of integrin-β1 prevents the development of polycystic kidney disease after the loss of Polycystin-1. J Am Soc Nephrol 26:888–895

    Article  CAS  PubMed  Google Scholar 

  • Lee KL, Guevarra MD, Nguyen AM, Chua MC, Wang Y, Jacobs CR (2015b) The primary cilium functions as a mechanical and calcium signaling nexus. Cilia 4:7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Luo Y, Starremans PG, McNamara CA, Pei Y, Zhou J (2005) Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat Cell Biol 7:1202–1212

    Article  PubMed  CAS  Google Scholar 

  • Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LSB, Somlo S, Igarashi P (2003) Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci U S A 100:5286–5291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Logue SE, Elgendy M, Martin SJ (2009) Expression, purification and use of recombinant annexin V for the detection of apoptotic cells. Nat Protoc 4:1383–1395

    Article  CAS  PubMed  Google Scholar 

  • Martin-Belmonte F, Mostov K (2008) Regulation of cell polarity during epithelial morphogenesis. Curr Opin Cell Biol 20:227–234

    Article  CAS  PubMed  Google Scholar 

  • Mattson MP, Chan SL (2003) Calcium orchestrates apoptosis. Nat Cell Biol 5:1041–1043

    Article  CAS  PubMed  Google Scholar 

  • Montessuit S, Somasekharan SP, Terrones O, Lucken-Ardjomande S, Herzig S, Schwarzenbacher R, Manstein DJ, Bossy-Wetzel E, Basañez G, Meda P, Martinou J-C (2010) Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell 142:889–901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moser M, Pscherer A, Roth C, Becker J, Mücher G, Zerres K, Dixkens C, Weis J, Guay-Woodford L, Buettner R, Fässler R (1997) Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2β. Genes Dev 11:1938–1948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nachbur U, Silke J (2016) Killing lymphoma with Smac-mimetics: as easy as ABC? Cancer Cell 29:425–427

    Article  CAS  PubMed  Google Scholar 

  • Nagao S, Morita M, Kugita M, Yoshihara D, Yamaguchi T, Kurahashi H, Calvet JP, Wallace DP (2010) Polycystic kidney disease in Han:SPRD cy rats is associated with elevated expression and mislocalization of SamCystin. Am J Physiol Ren Physiol 299:F1078–F1086

    Article  CAS  Google Scholar 

  • Nakayama K, Nakayama K, Negishi I, Kuida K, Shinkai Y, Louie M, Fields L, Lucas P, Stewart V, Alt F et al (1993) Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. Science 261:1584–1588

    Article  CAS  PubMed  Google Scholar 

  • Nauta J, Goedbloed MA, Luider TM, Hoogeveen AT, van den Ouweland AMW, Halley DJJ (1997) The Han:SPRD rat is not a genetic model of human autosomal dominant polycystic kidney disease type 1. Lab Anim 31:241–247

    Article  CAS  PubMed  Google Scholar 

  • Nicholls SB, Hyman BT (2014) Measuring caspase activity in vivo. Methods Enzymol 544:251–269

    Article  CAS  PubMed  Google Scholar 

  • Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, Munday NA, Raju SM, Smulson ME, Yamin T-T, Yu VL, Miller DK (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37–43

    Article  CAS  PubMed  Google Scholar 

  • Nishio S, Masahiko H, Nagata M, Horie S, Koike T, Tokuhisa T, Mochizuki T (2005) Pkd1 regulates immortalized proliferation af renal tubular epithelial cells through p53 induction and JNK activation. J Clin Invest 115:910–919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, Masuyama N, Gotoh Y (2002) Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem 277:21843–21850

    Article  CAS  PubMed  Google Scholar 

  • Oviedo-Boyso J, Cortés-Vieyra R, Huante-Mendoza A, Yu HB, Valdez-Alarcón JJ, Bravo-Patiño A, Cajero-Juárez M, Finlay BB, Baizabal-Aguirre VM (2011) The phosphoinositide-3-kinase–Akt signaling pathway is important for Staphylococcus aureus internalization by endothelial cells. Infect Immun 79:4569–4577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paoli P, Giannoni E, Chiarugi P (2013) Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta 1833:3481–3498

    Article  CAS  PubMed  Google Scholar 

  • Parnell SC, Magenheimer BS, Maser RL, Zien CA, Frischauf AM, Calvet JP (2002) Polycystin-1 activation of c-Jun N-terminal kinase and AP-1 is mediated by heterotrimeric G proteins. J Biol Chem 277:19566–19572

    Article  CAS  PubMed  Google Scholar 

  • Pasparakis M, Vandenabeele P (2015) Necroptosis and its role in inflammation. Nature 517:311–320

    Article  CAS  PubMed  Google Scholar 

  • Peintner L, Dorstyn L, Kumar S, Aneichyk T, Villunger A, Manzl C (2015) The tumor-modulatory effects of caspase-2 and Pidd1 do not require the scaffold protein Raidd. Cell Death Differ 22:1803–1811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pema M, Drusian L, Chiaravalli M, Castelli M, Yao Q, Ricciardi S, Somlo S, Qian F, Biffo S, Boletta A (2016) mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex. Nat Commun 7:10786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peyronnet R, Sharif-Naeini R, Folgering J, Arhatte M, Jodar M, El Boustany C, Gallian C, Tauc M, Duranton C, Rubera I, Lesage F, Pei Y, Peters Dorien JM, Somlo S, Sachs F, Patel A, Honoré E, Duprat F (2012) Mechanoprotection by polycystins against apoptosis is mediated through the opening of stretch-activated K2P channels. Cell Rep 1:241–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pinon JD, Labi V, Egle A, Villunger A (2008) Bim and Bmf in tissue homeostasis and malignant disease. Oncogene 27:S41–S52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piontek KB, Huso DL, Grinberg A, Liu L, Bedja D, Zhao H, Gabrielson K, Qian F, Mei C, Westphal H, Germino GG (2004) A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo. J Am Soc Nephrol 15:3035–3043

    Article  PubMed  Google Scholar 

  • Qian F, Boletta A, Bhunia AK, Xu H, Liu L, Ahrabi AK, Watnick TJ, Zhou F, Germino GG (2002) Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations. Proc Natl Acad Sci U S A 99:16981–16986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ricci J-E, Muñoz-Pinedo C, Fitzgerald P, Bailly-Maitre B, Perkins GA, Yadava N, Scheffler IE, Ellisman MH, Green DR (2004) Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117:773–786

    Article  CAS  PubMed  Google Scholar 

  • Roberts AW, Stilgenbauer S, Seymour JF, Huang DCS (2017) Venetoclax in patients with previously treated chronic lymphocytic leukemia. Clin Cancer Res (in press)

  • Rowe I, Chiaravalli M, Mannella V, Ulisse V, Quilici G, Pema M, Song XW, Xu H, Mari S, Qian F, Pei Y, Musco G, Boletta A (2013) Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat Med 19:488–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schlicher L, Wissler M, Preiss F, Brauns-Schubert P, Jakob C, Dumit V, Borner C, Dengjel J, Maurer U (2016) SPATA2 promotes CYLD activity and regulates TNF induced NFκB signaling and cell death. EMBO Rep 17:1485–1497

    Article  CAS  PubMed  Google Scholar 

  • Simms RJ, Ong ACM (2014) How simple are “simple renal cysts”? Nephrol Dial Transplant 29:iv106–iv112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sorenson C, Rogers S, Korsmeyer SJ, Hammerman M (1995) Fulminant metanephric apoptosis and abnormal kidney development in bcl-2 deficient mice. Am Physiol Soc 268:73–81

    Google Scholar 

  • Subburaj Y, Cosentino K, Axmann M, Pedrueza-Villalmanzo E, Hermann E, Bleicken S, Spatz J, García-Sáez AJ (2015) Bax monomers form dimer units in the membrane that further self-assemble into multiple oligomeric species. Nat Commun 6:8042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X (2012) Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148:213–227

    Article  CAS  PubMed  Google Scholar 

  • Torres VE, Harris PC (2014) Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J Am Soc Nephrol 25:18–32

    Article  CAS  PubMed  Google Scholar 

  • Torres VE, Harris PC, Pirson Y (2007) Autosomal dominant polycystic kidney disease. Lancet 369:1287–1307

    Article  PubMed  Google Scholar 

  • Trudel M (2015) c-Myc signalling in the genetic mechanism of polycystic kidney disease. In: Li X (ed) Polycystic kidney disease [Internet]. Codon, Brisbane. 10.15586/codon.pkd.2015.ch10

    Google Scholar 

  • Trudel M, Lanoix J, Barisoni L, Blouin M-J, Desforges M, L’Italien C, D’Agati V (1997) C-MYC–induced apoptosis in polycystic kidney disease is Bcl-2 and p53 independent. J Exp Med 186:1873–1884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trudel M, Barisoni L, Lanoix J, D’Agati V (1998) Polycystic kidney disease in SBM transgenic mice: role of c-myc in disease induction and progression. Am J Pathol 152:219–229

    CAS  PubMed  PubMed Central  Google Scholar 

  • Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ (1993) Bcl2 deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75:229–240

    Article  CAS  PubMed  Google Scholar 

  • Vitale I, Galluzzi L, Castedo M, Kroemer G (2011) Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat Rev Mol Cell Biol 12:385–392

    Article  CAS  PubMed  Google Scholar 

  • Wegierski T, Steffl D, Kopp C, Tauber R, Buchholz B, Nitschke R, Kuehn W, Walz G, Köttgen M (2009) TRPP2 channels regulate apoptosis through the Ca2+ concentration in the endoplasmic reticulum. EMBO J 28:490–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei F, Karihaloo A, Yu Z, Marlier A, Seth P, Shibazaki S, Wang T, Sukhatme VP, Somlo S, Cantley LG (2008) Neutrophil gelatinase-associated lipocalin suppresses cyst growth by Pkd1 null cells in vitro and in vivo. Kidney Int 74:1310–1318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weinlich R, Oberst A, Beere HM, Green DR (2017) Necroptosis in development, inflammation and disease. Nat Rev Mol Cell Biol 18:127–136

    Article  CAS  PubMed  Google Scholar 

  • Weston BS, Jeffery S, Jeffrey I, Sharaf SFA, Carter N, Saggar-Malik A, Price RG (1997) Polycystin expression during embryonic development of human kidney in adult tissues and ADPKD tissue. Histochem J 29:847–856

    Article  CAS  PubMed  Google Scholar 

  • Wilson PD (2004a) Mechanisms of disease: polycystic kidney disease. N Engl J Med 350:151–164

    Article  CAS  PubMed  Google Scholar 

  • Wilson PD (2004b) Polycystic kidney disease: new understanding in the pathogenesis. Int J Biochem Cell B 36:1868–1873

    Article  CAS  Google Scholar 

  • Wodarczyk C, Distefano G, Rowe I, Gaetani M, Bricoli B, Muorah M, Spitaleri A, Mannella V, Ricchiuto P, Pema M, Castelli M, Casanova AE, Mollica L, Banzi M, Boca M, Antignac C, Saunier S, Musco G, Boletta A (2010) Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals. PLoS One 5:e12719

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Woo D (1995) Apoptosis and loss of renal tissue in polycystic kidney diseases. N Engl J Med 333:18–25

    Article  CAS  PubMed  Google Scholar 

  • Xu JX, Lu T-S, Li S, Wu Y, Ding L, Denker BM, Bonventre JV, Kong T (2015) Polycystin-1 and Gα12 regulate the cleavage of E-cadherin in kidney epithelial cells. Physiol Genomics 47:24–32

    Article  CAS  PubMed  Google Scholar 

  • Yao G, Su X, Nguyen V, Roberts K, Li X, Takakura A, Plomann M, Zhou J (2014) Polycystin-1 regulates actin cytoskeleton organization and directional cell migration through a novel PC1-Pacsin 2-N-wasp complex. Hum Mol Genet 23:2769–2779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Li L, Liu R, Shu B, Chen H, Huang H, Hua R, Jiang F, An Y (2016) Autophagy in long propriospinal neurons is activated after spinal cord injury in adult rats. Neurosci Lett 634:138–145

    Article  CAS  PubMed  Google Scholar 

  • Yu S, Hackmann K, Gao J, He X, Piontek K, García-González MA, Menezes LF, Xu H, Germino GG, Zuo J, Qian F (2007) Essential role of cleavage of polycystin-1 at G protein-coupled receptor proteolytic site for kidney tubular structure. Proc Natl Acad Sci U S A 104:18688–18693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan J, Najafov A, Py BF (2016) Roles of caspases in necrotic cell death. Cell 167:1693–1704

    Article  CAS  PubMed  Google Scholar 

  • Zhang Q-L, Rothenbacher D (2008) Prevalence of chronic kidney disease in population-based studies: systematic review. BMC Public Health 8:1–13

    Article  CAS  Google Scholar 

  • Zhou D, Tan RJ, Fu H, Liu Y (2016) Wnt/β-catenin signaling in kidney injury and repair: a double-edged sword. Lab Invest 96:156–167

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Our research is funded by the Collaborative Research Center (SFB) KIDGEM 1140 “Kidney Disease – From Genes to Mechanisms” of the Deutsche Forschungsgemeinschaft (DFG).

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  1. Institute of Molecular Medicine and Cell Research, Albert Ludwigs University of Freiburg, Stefan Meier Strasse 17, 79104, Freiburg, Germany

    Lukas Peintner & Christoph Borner

  2. Spemann Graduate School of Biology and Medicine, Albert Ludwigs University of Freiburg, Albertstrasse 19a, 79104, Freiburg, Germany

    Christoph Borner

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  1. Lukas Peintner
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Peintner, L., Borner, C. Role of apoptosis in the development of autosomal dominant polycystic kidney disease (ADPKD). Cell Tissue Res 369, 27–39 (2017). https://doi.org/10.1007/s00441-017-2628-6

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