Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.
ADPKD
Antisense Oligonucleotides
Glutamine Metabolism
Glycolysis
Metabolic Reprogramming
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
29 Apr 2024
29 Apr 2024
Historique:
received:
06
10
2023
accepted:
12
04
2024
revised:
11
04
2024
medline:
30
4
2024
pubmed:
30
4
2024
entrez:
29
4
2024
Statut:
aheadofprint
Résumé
Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4-ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.
Identifiants
pubmed: 38684863
doi: 10.1038/s44321-024-00071-9
pii: 10.1038/s44321-024-00071-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
ID : RF-2018-12368254
Organisme : Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
ID : GR-2016-02364851
Organisme : Fondazione AIRC per la ricerca sul cancro ETS (AIRC)
ID : IG2019-23513
Informations de copyright
© 2024. The Author(s).
Références
Baliga MM, Klawitter J, Christians U, Hopp K, Chonchol M, Gitomer BY, Cadnapaphornchai MA, Klawitter J (2021) Metabolic profiling in children and young adults with autosomal dominant polycystic kidney disease. Sci Rep 11:6629
pubmed: 33758231
pmcid: 7988179
doi: 10.1038/s41598-021-84609-8
Bergmann C, Guay-Woodford LM, Harris PC, Horie S, Peters DJM, Torres VE (2018) Polycystic kidney disease. Nat Rev Dis Prim 4:50
pubmed: 30523303
doi: 10.1038/s41572-018-0047-y
Chiaravalli M, Rowe I, Mannella V, Quilici G, Canu T, Bianchi V, Gurgone A, Antunes S, D’Adamo P, Esposito A et al (2016) 2-Deoxy-D-glucose ameliorates PKD progression. J Am Soc Nephrol 27:1958–1969
pubmed: 26534924
doi: 10.1681/ASN.2015030231
Chiu M, Taurino G, Bianchi MG, Kilberg MS, Bussolati O (2020) Asparagine synthetase in cancer: beyond acute lymphoblastic leukemia. Front Oncol 9:1480
pubmed: 31998641
pmcid: 6962308
doi: 10.3389/fonc.2019.01480
Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G, Wishart DS, Xia J (2018) MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res 46:gky310
doi: 10.1093/nar/gky310
Clasquin MF, Melamud E, Rabinowitz JD (2012) LC‐MS data processing with MAVEN: a metabolomic analysis and visualization engine. Curr Protoc Bioinform 37:14.11.1–14.11.23
doi: 10.1002/0471250953.bi1411s37
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(9):2359–2371
Fedeles SV, So J-S, Shrikhande A, Lee SH, Gallagher A-R, Barkauskas CE, Somlo S, Lee A-H (2015) Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity. J Clin Investig 125:1955–1967
pubmed: 25844898
pmcid: 4463201
doi: 10.1172/JCI78863
Flowers EM, Sudderth J, Zacharias L, Mernaugh G, Zent R, DeBerardinis RJ, Carroll TJ (2018) Lkb1 deficiency confers glutamine dependency in polycystic kidney disease. Nat Commun 9:814
pubmed: 29483507
pmcid: 5827653
doi: 10.1038/s41467-018-03036-y
Gaeggeler H-P, Gonzalez-Rodriguez E, Jaeger NF, Loffing-Cueni D, Norregaard R, Loffing J, Horisberger J-D, Rossier BC (2005) Mineralocorticoid versus glucocorticoid receptor occupancy mediating aldosterone-stimulated sodium transport in a novel renal cell line. J Am Soc Nephrol 16:878–891
pubmed: 15743993
doi: 10.1681/ASN.2004121110
Gu Z, Eils R, Schlesner M (2016) Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32:2847–2849
pubmed: 27207943
doi: 10.1093/bioinformatics/btw313
Gutierrez JA, Pan Y-X, Koroniak L, Hiratake J, Kilberg MS, Richards NGJ (2006) An inhibitor of human asparagine synthetase suppresses proliferation of an L-asparaginase-resistant leukemia cell line. Chem Biol 13:1339–1347
pubmed: 17185229
pmcid: 3608209
doi: 10.1016/j.chembiol.2006.10.010
Harris PC, Torres VE (2014) Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease. J Clin Investig 124:2315–2324
pubmed: 24892705
pmcid: 4089452
doi: 10.1172/JCI72272
Hopp K, Ward CJ, Hommerding CJ, Nasr SH, Tuan H-F, Gainullin VG, Rossetti S, Torres VE, Harris PC (2012) Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J Clin Investig 122:4257–4273
pubmed: 23064367
pmcid: 3484456
doi: 10.1172/JCI64313
Jin H-O, Hong S-E, Kim J-Y, Jang S-K, Park I-C (2021) Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis. Cell Death Dis 12:1127
pubmed: 34862383
pmcid: 8642548
doi: 10.1038/s41419-021-04417-w
Kanno A, Asahara S, Furubayashi A, Masuda K, Yoshitomi R, Suzuki E, Takai T, Kimura-Koyanagi M, Matsuda T, Bartolome A et al (2020) GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels. JCI Insight 5:e128820
pubmed: 32376799
pmcid: 7253016
doi: 10.1172/jci.insight.128820
Krall AS, Mullen PJ, Surjono F, Momcilovic M, Schmid EW, Halbrook CJ, Thambundit A, Mittelman SD, Lyssiotis CA, Shackelford DB et al (2021) Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth. Cell Metab 33:1013–1026.e6
pubmed: 33609439
pmcid: 8102379
doi: 10.1016/j.cmet.2021.02.001
Krall AS, Xu S, Graeber TG, Braas D, Christofk HR (2016) Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat Commun 7:11457
pubmed: 27126896
pmcid: 4855534
doi: 10.1038/ncomms11457
Leeuwen ISL, Dauwerse JG, Baelde HJ, Leonhard WN, Wal A, van de, Ward CJ, Verbeek S, DeRuiter MC, Breuning MH, Heer Ede et al (2004) Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum Mol Genet 13:3069–3077
doi: 10.1093/hmg/ddh336
Leeuwen ISL, Leonhard WN, Wal A, van der, Breuning MH, Heer Ede, Peters DJM (2007) Kidney-specific inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. Hum Mol Genet 16:3188–3196
doi: 10.1093/hmg/ddm299
Lian X, Wu X, Li Z, Zhang Y, Song K, Cai G, Li Q, Lin S, Chen X, Bai X (2019) The combination of metformin and 2‐deoxyglucose significantly inhibits cyst formation in miniature pigs with polycystic kidney disease. Br J Pharm 176:711–724
doi: 10.1111/bph.14558
Lin C-C, Kurashige M, Liu Y, Terabayashi T, Ishimoto Y, Wang T, Choudhary V, Hobbs R, Liu L-K, Lee P-H et al (2018) A cleavage product of Polycystin-1 is a mitochondrial matrix protein that affects mitochondria morphology and function when heterologously expressed. Sci Rep 8:2743
pubmed: 29426897
pmcid: 5807443
doi: 10.1038/s41598-018-20856-6
Lin C-C, Menezes LF, Qiu J, Pearson E, Zhou F, Ishimoto Y, Anderson DE, Germino GG (2023) In vivo Polycystin-1 interactome using a novel Pkd1 knock-in mouse model. PLoS ONE 18:e0289778
pubmed: 37540694
pmcid: 10403143
doi: 10.1371/journal.pone.0289778
Lomelino CL, Andring JT, McKenna R, Kilberg MS (2017) Asparagine synthetase: Function, structure, and role in disease. J Biol Chem 292:19952–19958
pubmed: 29084849
pmcid: 5723983
doi: 10.1074/jbc.R117.819060
Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S (2013) Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat Genet 45:1004–1012
pubmed: 23892607
pmcid: 3758452
doi: 10.1038/ng.2715
Menezes LF, Lin C-C, Zhou F, Germino GG (2016) Fatty acid oxidation is impaired in an orthologous mouse model of autosomal dominant polycystic kidney disease. Ebiomedicine 5:183–192
pubmed: 27077126
pmcid: 4816756
doi: 10.1016/j.ebiom.2016.01.027
Milman HA, Cooney DA (1974) The distribution of l -asparagine synthetase in the principal organs of several mammalian and avian species. Biochem J 142:27–35
pubmed: 4216348
pmcid: 1168207
doi: 10.1042/bj1420027
Montesano R, Ghzili H, Carrozzino F, Rossier BC, Féraille E (2009) cAMP-dependent chloride secretion mediates tubule enlargement and cyst formation by cultured mammalian collecting duct cells. Am J Physiol-Ren Physiol 296:F446–F457
doi: 10.1152/ajprenal.90415.2008
Muto Y, Wilson PC, Ledru N, Wu H, Dimke H, Waikar SS, Humphreys BD (2021) Single cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney. Nat Commun 12:2190
pubmed: 33850129
pmcid: 8044133
doi: 10.1038/s41467-021-22368-w
Nemkov T, Hansen KC, D’Alessandro A (2017) A three‐minute method for high‐throughput quantitative metabolomics and quantitative tracing experiments of central carbon and nitrogen pathways. Rapid Commun Mass Spectrom 31:663–673
pubmed: 28195377
pmcid: 5364945
doi: 10.1002/rcm.7834
Nikonova AS, Deneka AY, Kiseleva AA, Korobeynikov V, Gaponova A, Serebriiskii IG, Kopp MC, Hensley HH, Seeger‐Nukpezah TN, Somlo S et al (2018) Ganetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD). FASEB J 32:2735–2746
pubmed: 29401581
pmcid: 5901382
doi: 10.1096/fj.201700909R
Olson RJ, Hopp K, Wells H, Smith JM, Furtado J, Constans MM, Escobar DL, Geurts AM, Torres VE, Harris PC (2019) Synergistic genetic interactions between Pkhd1 and Pkd1 result in an ARPKD-like phenotype in murine models. J Am Soc Nephrol 30:2113–2127
pubmed: 31427367
pmcid: 6830782
doi: 10.1681/ASN.2019020150
Ong ACM, Harris PC (2015) A polycystin-centric view of cyst formation and disease: the polycystins revisited. Kidney Int 88:699–710
pubmed: 26200945
pmcid: 4589452
doi: 10.1038/ki.2015.207
Onuchic L, Padovano V, Schena G, Rajendran V, Dong K, Shi X, Pandya R, Rai V, Gresko NP, Ahmed O et al (2023) The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion. Nat Commun 14:1790
pubmed: 36997516
pmcid: 10063565
doi: 10.1038/s41467-023-37449-1
Padovano V, Kuo IY, Stavola LK, Aerni HR, Flaherty BJ, Chapin HC, Ma M, Somlo S, Boletta A, Ehrlich BE et al (2017) The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function. Mol Biol Cell 28:261–269
pubmed: 27881662
pmcid: 5231895
doi: 10.1091/mbc.e16-08-0597
Panda DK, Bai X, Zhang Y, Stylianesis NA, Koromilas AE, Lipman ML, Karaplis AC (2022) SCF-SKP2 E3 ubiquitin ligase links mTORC1-ER stress-ISR with YAP activation in murine renal cystogenesis. J Clin Investig 132:e153943
pubmed: 36326820
pmcid: 9754004
doi: 10.1172/JCI153943
Pellegrini H, Sharpe EH, Liu G, Nishiuchi E, Doerr N, Kipp KR, Chin T, Schimmel MF, Weimbs T (2023) Cleavage fragments of the C-terminal tail of polycystin-1 are regulated by oxidative stress and induce mitochondrial dysfunction. J Biol Chem 299:105158
pubmed: 37579949
pmcid: 10502374
doi: 10.1016/j.jbc.2023.105158
Piontek K, Menezes LF, Garcia-Gonzalez MA, Huso DL, Germino GG (2007) A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med 13:1490–1495
pubmed: 17965720
pmcid: 2302790
doi: 10.1038/nm1675
Podrini C, Cassina L, Boletta A (2020) Metabolic reprogramming and the role of mitochondria in polycystic kidney disease. Cell Signal 67:109495
pubmed: 31816397
doi: 10.1016/j.cellsig.2019.109495
Podrini C, Rowe I, Pagliarini R, Costa ASH, Chiaravalli M, Meo ID, Kim H, Distefano G, Tiranti V, Qian F et al (2018) Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways. Commun Biol 1:194
pubmed: 30480096
pmcid: 6240072
doi: 10.1038/s42003-018-0200-x
Qian F, Watnick TJ, Onuchic LF, Germino GG (1996) The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell 87:979–987
pubmed: 8978603
doi: 10.1016/S0092-8674(00)81793-6
Ramalingam H, Kashyap S, Cobo-Stark P, Flaten A, Chang C-M, Hajarnis S, Hein KZ, Lika J, Warner GM, Espindola-Netto JM et al (2021) A methionine-Mettl3-N 6 -methyladenosine axis promotes polycystic kidney disease. Cell Metab 33:1234–1247.e7
pubmed: 33852874
pmcid: 8172529
doi: 10.1016/j.cmet.2021.03.024
Reisz JA, Zheng C, D’Alessandro A, Nemkov T (2019) High-throughput metabolomics, methods and protocols. Methods Mol Biol 1978:121–135
pubmed: 31119660
doi: 10.1007/978-1-4939-9236-2_8
Riwanto M, Kapoor S, Rodriguez D, Edenhofer I, Segerer S, Wüthrich RP (2016) Inhibition of aerobic glycolysis attenuates disease progression in polycystic kidney disease. PLoS ONE 11:e0146654
pubmed: 26752072
pmcid: 4708993
doi: 10.1371/journal.pone.0146654
Rowe I, Chiaravalli M, Mannella V, Ulisse V, Quilici G, Pema M, Song XW, Xu H, Mari S, Qian F et al (2013) Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat Med 19:488–493
pubmed: 23524344
pmcid: 4944011
doi: 10.1038/nm.3092
Roy SG, Li Z, Guo Z, Long KT, Rehrl S, Tian X, Dong K, Besse W (2023) Dnajb11-kidney disease develops from reduced polycystin-1 dosage but not unfolded protein response in mice. J Am Soc Nephrol 34:1521–1534
doi: 10.1681/ASN.0000000000000164
Song X, Giovanni VD, He N, Wang K, Ingram A, Rosenblum ND, Pei Y (2009) Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks. Hum Mol Genet 18:2328–2343
pubmed: 19346236
doi: 10.1093/hmg/ddp165
Soomro I, Sun Y, Li Z, Diggs L, Hatzivassiliou G, Thomas AG, Rais R, Parker SJ, Slusher BS, Kimmelman AC et al (2018) Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease. Nephrol Dial Transpl 33:1343–1353
doi: 10.1093/ndt/gfx349
Steidl ME, Nigro EA, Nielsen AK, Pagliarini R, Cassina L, Lampis M, Podrini C, Chiaravalli M, Mannella V, Distefano G et al (2023) Primary cilia sense glutamine availability and respond via asparagine synthetase. Nat Metab 5:385–397
pubmed: 36879119
pmcid: 10042734
doi: 10.1038/s42255-023-00754-6
Su X, Lu W, Rabinowitz JD (2017) Metabolite spectral accuracy on orbitraps. Anal Chem 89:5940–5948
pubmed: 28471646
pmcid: 5748891
doi: 10.1021/acs.analchem.7b00396
Sullivan LB, Gui DY, Hosios AM, Bush LN, Freinkman E, Vander Heiden MG (2015) Supporting aspartate biosynthesis is an essential function of respiration in proliferating. Cells Cell 162:552–563
pubmed: 26232225
doi: 10.1016/j.cell.2015.07.017
Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade RD, Blais JD, Czerwiec FS et al (2017) Tolvaptan in later-stage autosomal dominant polycystic kidney disease. New Engl J Med 377:1930–1942
pubmed: 29105594
doi: 10.1056/NEJMoa1710030
Torres VE, Harris PC, Pirson Y (2007) Autosomal dominant polycystic kidney disease. Lancet 369:1287–1301
pubmed: 17434405
doi: 10.1016/S0140-6736(07)60601-1
Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A et al (2015) Tissue-based map of the human proteome. Science 347:1260419
pubmed: 25613900
doi: 10.1126/science.1260419
Watkins PB, Lewis JH, Kaplowitz N, Alpers DH, Blais JD, Smotzer DM, Krasa H, Ouyang J, Torres VE, Czerwiec FS et al (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
pubmed: 26188764
pmcid: 4608984
doi: 10.1007/s40264-015-0327-3
Watnick T, He N, Wang K, Liang Y, Parfrey P, Hefferton D, George-Hyslop PS, Germino G, Pei Y (2000) Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations. Nat Genet 25:143–144
pubmed: 10835625
doi: 10.1038/75981
Wodarczyk C, Rowe I, Chiaravalli M, Pema M, Qian F, Boletta A (2009) A novel mouse model reveals that polycystin-1 deficiency in ependyma and choroid plexus results in dysfunctional cilia and hydrocephalus. PLoS ONE 4:e7137
pubmed: 19774080
pmcid: 2743994
doi: 10.1371/journal.pone.0007137
Wu H, Villalobos RG, Yao X, Reilly D, Chen T, Rankin M, Myshkin E, Breyer MD, Humphreys BD (2022) Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies. Cell Metab 34:1064–1078.e6
pubmed: 35709763
pmcid: 9262852
doi: 10.1016/j.cmet.2022.05.010