Glucosylceramide synthase modulation ameliorates murine renal pathologies and promotes macrophage effector function in vitro.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
02 Aug 2024
02 Aug 2024
Historique:
received:
01
02
2024
accepted:
19
07
2024
medline:
3
8
2024
pubmed:
3
8
2024
entrez:
2
8
2024
Statut:
epublish
Résumé
While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8
Identifiants
pubmed: 39095617
doi: 10.1038/s42003-024-06606-7
pii: 10.1038/s42003-024-06606-7
doi:
Substances chimiques
Glucosyltransferases
EC 2.4.1.-
ceramide glucosyltransferase
EC 2.4.1.80
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
932Informations de copyright
© 2024. The Author(s).
Références
Romagnani, P. Chronic kidney disease. Nat. Rev. 3, 17088 (2017).
Zhang, T., de Waard, A. A., Wuhrer, M. & Spaapen, R. M. The role of glycosphingolipids in immune cell functions. Front. Immunol. 10, 90 (2019).
pubmed: 30761148
pmcid: 6361815
doi: 10.3389/fimmu.2019.00090
D'Angelo, G., Capasso, S., Sticco, L. & Russo, D. Glycosphingolipids: synthesis and functions. FEBS J. 280, 6338–6353 (2013).
pubmed: 24165035
doi: 10.1111/febs.12559
Zhu, Y. et al. Lowering glycosphingolipid levels in CD4+ T cells attenuates T cell receptor signaling, cytokine production, and differentiation to the Th17 lineage. J. Biol. Chem. 286, 14787–14794 (2011).
pubmed: 21402703
pmcid: 3083190
doi: 10.1074/jbc.M111.218610
Tsai, B., Gilbert, J. M., Stehle, T. & Lencer, W. Gangliosides are receptors for murine polyoma virus and SV40. EMBO J. 22, 4346–4355 (2003).
pubmed: 12941687
pmcid: 202381
doi: 10.1093/emboj/cdg439
Takenouchi, H. & Kiyokawa, N. Shiga toxin binding to globotriaosyl ceramide induces intracellular signals that mediate cytoskeleton remodeling in human renal carcinoma-derived cells. J. Cell Sci. 117, 3911–3922 (2004).
pubmed: 15265987
doi: 10.1242/jcs.01246
Nakayama, H. et al. The regulatory roles of glycosphingolipid-enriched lipid rafts in immune systems. FEBS Lett. 592, 3921–3942 (2018).
pubmed: 30320884
doi: 10.1002/1873-3468.13275
Breiden, B. & Sandhoff, K. Lysosomal glycosphingolipid storage diseases. Annu. Rev. Biochem. 88, 461–485 (2019).
pubmed: 31220974
doi: 10.1146/annurev-biochem-013118-111518
Alam, S., Fedier, A., Kohler, R. S. & Jacob, F. Glucosylceramide synthase inhibitors differentially affect expression of glycosphingolipids. Glycobiology 25, 351–356 (2015).
pubmed: 25715344
doi: 10.1093/glycob/cwu187
Jimbo, M. & Yamagishi, K. Development of a new inhibitor of glucosylceramide synthase. J. Biochem. 127, 485–491 (2000).
pubmed: 10731721
doi: 10.1093/oxfordjournals.jbchem.a022631
Natoli, T. A., Smith, L. A. & Rogers, K. A. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat. Med. 16, 788–792 (2010).
pubmed: 20562878
pmcid: 3660226
doi: 10.1038/nm.2171
Blumenreich, S. Substrate reduction therapy using Genz-667161 reduces levels of pathogenic components in a mouse model of neuronopathic forms of Gaucher disease. J. Neurochem. 156, 692–701 (2021).
pubmed: 32743826
doi: 10.1111/jnc.15136
Viel, C. Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model. Sci. Rep. 11, 20945 (2021).
pubmed: 34686711
pmcid: 8536659
doi: 10.1038/s41598-021-00404-5
Anuraga, G. & Wang, W. J. Potential prognostic biomarkers of NIMA (never in mitosis, gene a)-related kinase (NEK) family members in breast cancer. J. Pers. Med. 11, 1089 (2021).
pubmed: 34834441
pmcid: 8625415
doi: 10.3390/jpm11111089
Smith, L. A. Development of polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease. JASN 17, 2821–2831 (2006).
pubmed: 16928806
doi: 10.1681/ASN.2006020136
Sardi, S. P. Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models. PNAS 114, 2699–2704 (2017).
pubmed: 28223512
pmcid: 5347608
doi: 10.1073/pnas.1616152114
Cosgrove, D. et al. Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome. Genes Dev. 10, 2981–2992 (1996).
pubmed: 8956999
doi: 10.1101/gad.10.23.2981
Andrews, K. L. Quantitative trait loci influence renal disease progression in a mouse model of Alport syndrome. Am. J. Pathol. 160, 721–730 (2002).
pubmed: 11839593
pmcid: 1850644
doi: 10.1016/S0002-9440(10)64892-4
Mollet, G. & Ratelade, J. Podocin inactivation in mature kidneys causes focal segmental glomerulosclerosis and nephrotic syndrome. JASN 20, 2181–2189 (2009).
pubmed: 19713307
pmcid: 2754108
doi: 10.1681/ASN.2009040379
Ding, W., Yousefi, K. & Goncalves, S. Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits. JCI Insight 3, e94818 (2018).
pubmed: 29563333
pmcid: 5926939
doi: 10.1172/jci.insight.94818
Zalli, D. The Nek8 protein kinase, mutated in the human cystic kidney disease nephronophthisis, is both activated and degraded during ciliogenesis. Hum. Mol. Genet. 21, 1155–1171 (2012).
pubmed: 22106379
doi: 10.1093/hmg/ddr544
Lehtonen, S. & Jalanko, H. Nephrin trafficking beyond the kidney—role in glucose–stimulated insulin secretion in β cells. JASN 27, 965–968 (2016).
pubmed: 26400568
doi: 10.1681/ASN.2015080960
Chen, E. Y. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14, 128 (2013).
pubmed: 23586463
pmcid: 3637064
doi: 10.1186/1471-2105-14-128
Kuleshov, M. V. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44, W90–W97 (2016).
pubmed: 27141961
pmcid: 4987924
doi: 10.1093/nar/gkw377
Xie, Z. Gene set knowledge discovery with enrichr. Curr. Protoc. 1, e90 (2021).
pubmed: 33780170
pmcid: 8152575
doi: 10.1002/cpz1.90
Jang, H. S. & Kim, J. I. Bone marrow-derived cells play a major role in kidney fibrosis via proliferation and differentiation in the infiltrated site. Biochim. Biophys. Acta 1832, 817–825 (2013).
pubmed: 23466592
doi: 10.1016/j.bbadis.2013.02.016
Mobarak, E. Glucosylceramide modifies the LPS-induced inflammatory response in macrophages and the orientation of the LPS/TLR4 complex in silico. Sci. Rep. 8, 13600 (2018).
pubmed: 30206272
pmcid: 6134110
doi: 10.1038/s41598-018-31926-0
Soto-Heredero, G. et al. Glycolysis – a key player in the inflammatory response. FEBS J. 287, 3350–3369 (2020).
pubmed: 32255251
pmcid: 7496292
doi: 10.1111/febs.15327
Guiteras, R. Macrophage in chronic kidney disease. Clin. Kidney J. 9, 765–771 (2016).
pubmed: 27994852
pmcid: 5162417
doi: 10.1093/ckj/sfw096
Li, X. A Tumor necrosis factor-alpha-mediated pathway promoting autosomal dominant polycystic kidney disease. Nat. Med. 14, 863–868 (2008).
pubmed: 18552856
pmcid: 3359869
doi: 10.1038/nm1783
Zheng, D. et al. Urinary excretion of monocyte chemoattractant protein-1 in autosomal dominant polycystic kidney disease. JASN 14, 2588–2595 (2003).
pubmed: 14514736
doi: 10.1097/01.ASN.0000088720.61783.19
Bieniaś, B. Early markers of tubulointerstitial fibrosis in children with idiopathic nephrotic syndrome: preliminary report. Med. (Baltim.) 94, e1746 (2015).
doi: 10.1097/MD.0000000000001746
Warady, B. A. Alport syndrome classification and management. Kidney Med. 2, 639–649 (2020).
pubmed: 33094278
pmcid: 7568086
doi: 10.1016/j.xkme.2020.05.014
Stathem, M. Glucose availability and glycolytic metabolism dictate glycosphingolipid levels. J. Cell. Biochem. 116, 67–80 (2015).
pubmed: 25145677
pmcid: 4229434
doi: 10.1002/jcb.24943
Wang, H. NEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation. Nat. Commun. 12, 4826 (2021).
pubmed: 34376696
pmcid: 8355301
doi: 10.1038/s41467-021-25157-7
Zhang, Y. & Wang, S. Identification of monocytes associated with severe COVID-19 in the PBMCs of severely infected patients through single-cell transcriptome sequencing. Engineering 17, 161–169 (2021).
pubmed: 34150352
doi: 10.1016/j.eng.2021.05.009
Liu, Y. Ganglioside depletion and EGF responses of human GM3 synthase-deficient fibroblasts. Glycobiology 18, 593–601 (2008).
pubmed: 18480157
doi: 10.1093/glycob/cwn039
Sharma, D. K. Selective stimulation of caveolar endocytosis by glycosphingolipids and cholesterol. Mol. Biol. Cell 15, 3114–3122 (2004).
pubmed: 15107466
pmcid: 452569
doi: 10.1091/mbc.e04-03-0189
Jennemann, R. Glycosphingolipids are essential for intestinal endocytic function. J. Biol. Chem. 287, 32598–32616 (2012).
pubmed: 22851168
pmcid: 3463339
doi: 10.1074/jbc.M112.371005
Gao P. Mitochondria-associated endoplasmic reticulum membranes (MAMs) and their prospective roles in kidney disease. Oxid. Med Cell. Longev. https://doi.org/10.1155/2020/3120539 (2020).
Batta, G. Alterations in the properties of the cell membrane due to glycosphingolipid accumulation in a model of Gaucher disease. Sci. Rep. 8, 157 (2018).
pubmed: 29317695
pmcid: 5760709
doi: 10.1038/s41598-017-18405-8
Lingwood, C. A. Glycosphingolipid functions. Cold Spring Harb. Perspect. Biol. 3, a004788 (2011).
pubmed: 21555406
pmcid: 3119914
doi: 10.1101/cshperspect.a004788
Parker, M. I., Nikonova, A. S., Sun, D. & Golemis, E. A. Proliferative signaling by ERBB proteins and RAF/MEK/ERK effectors in polycystic kidney disease. Cell. Signal. 67, 109497 (2020).
pubmed: 31830556
doi: 10.1016/j.cellsig.2019.109497
Wilson, P. D. Apico-basal polarity in polycystic kidney disease epithelia. Biochim. Biophys. Acta 1812, 1239–1248 (2011).
pubmed: 21658447
doi: 10.1016/j.bbadis.2011.05.008
Andersson, L. Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking. Eur. Heart J. 42, 4481–4492 (2021).
pubmed: 34297830
pmcid: 8599074
doi: 10.1093/eurheartj/ehab412
Atala, A., Freeman, M. R. & Mandell, J. Juvenile cystic kidneys (jck): a new mouse mutation which causes polycystic kidneys. Kidney Int. 43, 1081–1085 (1993).
pubmed: 8510385
doi: 10.1038/ki.1993.151
Gomez, I. G. Anti–microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J. Clin. Investig. 125, 141–156 (2015).
pubmed: 25415439
doi: 10.1172/JCI75852
Roselli, S. Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol. Cell. Biol. 24, 550–560 (2004).
pubmed: 14701729
pmcid: 343810
doi: 10.1128/MCB.24.2.550-560.2004
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. PNAS 102, 15545–15550 (2005).
pubmed: 16199517
pmcid: 1239896
doi: 10.1073/pnas.0506580102
Liberzon, A. & Subramanian, A. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739–1740 (2011).
pubmed: 21546393
pmcid: 3106198
doi: 10.1093/bioinformatics/btr260
Liberzon, A. et al. The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417–425 (2015).
pubmed: 26771021
pmcid: 4707969
doi: 10.1016/j.cels.2015.12.004
Finak, G., McDavid, A. & Yajima, M. MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol. 16, 278 (2015).
pubmed: 26653891
pmcid: 4676162
doi: 10.1186/s13059-015-0844-5
Aibar, S. et al. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083–1086 (2017).
pubmed: 28991892
pmcid: 5937676
doi: 10.1038/nmeth.4463
Kanehisa, M. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30 (2000).
pubmed: 10592173
pmcid: 102409
doi: 10.1093/nar/28.1.27
Kanehisa, M. Toward understanding the origin and evolution of cellular organisms. Protein Sci. 28, 1947–1951 (2019).
pubmed: 31441146
pmcid: 6798127
doi: 10.1002/pro.3715
Kanehisa, M. et al. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res. 49, D545–D551 (2021).
pubmed: 33125081
doi: 10.1093/nar/gkaa970
Wu, C. C. Integrative analysis of DiseaseLand omics database for disease signatures and treatments: a bipolar case study. Front. Genet. 10, 396 (2019).
pubmed: 31114610
pmcid: 6503737
doi: 10.3389/fgene.2019.00396
Korotkevich, G. et al. Fast gene set enrichment analysis. bioRxiv, https://www.biorxiv.org/content/10.1101/060012v3 (2021).
Durinck, S. BioMart and Bioconductor: a powerful link between biological databases and microarray data analysis. Bioinformatics 21, 3439–3440 (2005).
pubmed: 16082012
doi: 10.1093/bioinformatics/bti525
Durinck, S. Mapping identifiers for the integration of genomic datasets with the R/bioconductor package biomaRt. Nat. Protoc. 4, 1184–1191 (2009).
pubmed: 19617889
pmcid: 3159387
doi: 10.1038/nprot.2009.97
Muto, Y. Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis. Nat. Commun. 13, 6497 (2022).
pubmed: 36310237
pmcid: 9618568
doi: 10.1038/s41467-022-34255-z
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8