{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:15:48Z","timestamp":1790709348554,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T00:00:00Z","timestamp":1644710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008713","name":"Diabetes Australia Research Trust","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100008713","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001061","name":"Rebecca L. Cooper Medical Research Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100001061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Diabetic kidney disease (DKD) progresses at different rates among patients with type 2 diabetes mellitus (T2D). Early identification of patients with a higher risk of DKD progression is essential to improve prognosis. Epigenetic modifications, particularly DNA methylation, have been independently implicated in T2D and chronic kidney disease. The current study aimed to determine changes in blood DNA methylation that reflects and predicts DKD progression. C57BL\/6 mice were fed a high-fat diet (HFD) from weaning and subclassified into two groups, HFD-1 and HFD-2, according to urinary kidney injury marker KIM-1\/creatinine ratios (low vs. high) and histological abnormalities (mild\u2013moderate vs. advanced). DNA methylation profiles were determined by reduced representative bisulfide sequencing (RRBS). Our results confirmed early and established DKD at week 9 and week 32, respectively. At week 32, advanced kidney injury was associated with dysregulation of methylation and demethylation enzymes in the kidney. Blood RRBS revealed 579 and 203 differentially methylated sites (DMS) between HFD-1 and HFD-2 animals at week 32 and week 9, respectively, among which 11 were common. The DMS in blood and kidney at week 32 were both related to organ development, neurogenesis, cell junction, and Wnt signalling, while the DMS in blood at week 9 suggested a specific enrichment of kidney development processes. In conclusion, our data strongly support the implication of early blood DNA methylation modifications and DKD progression in T2D that could be used to improve the disease\u2019s prognostication.<\/jats:p>","DOI":"10.3390\/nu14040785","type":"journal-article","created":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T20:34:45Z","timestamp":1644784485000},"page":"785","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Blood DNA Methylation Predicts Diabetic Kidney Disease Progression in High Fat Diet-Fed Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0630-4959","authenticated-orcid":false,"given":"Long T.","family":"Nguyen","sequence":"first","affiliation":[{"name":"Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin P.","family":"Larkin","sequence":"additional","affiliation":[{"name":"Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosy","family":"Wang","sequence":"additional","affiliation":[{"name":"Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alen","family":"Faiz","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol A.","family":"Pollock","sequence":"additional","affiliation":[{"name":"Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Saad","sequence":"additional","affiliation":[{"name":"Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2006, Australia"},{"name":"School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,13]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021, October 25). Diabetes. Available online: https:\/\/www.who.int\/en\/news-room\/fact-sheets\/detail\/diabetes."},{"key":"ref_2","first-page":"49","article-title":"Diabetic kidney disease: World wide difference of prevalence and risk factors","volume":"5","author":"Gheith","year":"2016","journal-title":"J. Nephropharmacol."},{"key":"ref_3","first-page":"2032","article-title":"Diabetic Kidney Disease","volume":"12","author":"Alicic","year":"2017","journal-title":"Chall. Prog. Possibilities"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1007\/s11906-010-0133-3","article-title":"Is the presence of microalbuminuria a relevant marker of kidney disease?","volume":"12","author":"Glassock","year":"2010","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000333249","article-title":"Renal Dysfunction in the Presence of Normoalbuminuria in Type 2 Diabetes: Results from the DEMAND Study","volume":"2","author":"Dwyer","year":"2012","journal-title":"Cardiorenal Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/jdi.12533","article-title":"Clinical predictive factors in diabetic kidney disease progression","volume":"8","author":"Radcliffe","year":"2017","journal-title":"J. Diabetes Investig."},{"key":"ref_7","first-page":"E3002","article-title":"Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT\/EDIC type 1 diabetes cohort","volume":"113","author":"Chen","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1038\/s41467-017-01297-7","article-title":"Epigenome-wide association studies identify DNA methylation associated with kidney function","volume":"8","author":"Chu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1093\/ndt\/gft537","article-title":"DNA methylation profile associated with rapid decline in kidney function: Findings from the CRIC study","volume":"29","author":"Wing","year":"2014","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"561907","DOI":"10.3389\/fcell.2020.561907","article-title":"DNA methylation associated with diabetic kidney disease in Blood-Derived DNA","volume":"8","author":"Smyth","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1038\/emboj.2011.503","article-title":"DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients","volume":"31","author":"Volkmar","year":"2012","journal-title":"EMBO J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e3837","DOI":"10.1210\/clinem\/dgab488","article-title":"DNA Methylation Changes Associated With Type 2 Diabetes and Diabetic Kidney Disease in an East Asian Population","volume":"106","author":"Kim","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Nguyen, L.T., Mak, C.H., Chen, H., Zaky, A.A., Wong, M.G., Pollock, C.A., and Saad, S. (2019). SIRT1 Attenuates Kidney Disorders in Male Offspring Due to Maternal High-Fat Diet. Nutrients, 11.","DOI":"10.3390\/nu11010146"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1113\/JP276957","article-title":"SIRT1 overexpression attenuates offspring metabolic and liver disorders as a result of maternal high-fat feeding","volume":"597","author":"Nguyen","year":"2019","journal-title":"J. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Glastras, S.J., Chen, H., Tsang, M., Teh, R., McGrath, R.T., Zaky, A., Chen, J., Wong, M.G., Pollock, C.A., and Saad, S. (2017). The renal consequences of maternal obesity in offspring are overwhelmed by postnatal high fat diet. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172644"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1681\/ASN.2010080793","article-title":"Mechanisms of Tubulointerstitial Fibrosis","volume":"21","author":"Zeisberg","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1046\/j.1523-1755.2002.00433.x","article-title":"Kidney Injury Molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury","volume":"62","author":"Han","year":"2002","journal-title":"Kidney Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"525-P","DOI":"10.2337\/db18-525-P","article-title":"Urinary NGAL and KIM-1 Are Significantly Elevated in Young Adults (YA) with Type 1 (T1D) and Type 2 (T2D) Diabetes","volume":"67","author":"Sheanon","year":"2018","journal-title":"Diabetes"},{"key":"ref_19","first-page":"992","article-title":"Evaluation of kidney injury molecule-1 as a disease progression biomarker in diabetic nephropathy","volume":"35","author":"Khan","year":"2019","journal-title":"Pak. J. Med. Sci"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s40620-018-0556-5","article-title":"Circulating proteins as predictors of cardiovascular mortality in end-stage renal disease","volume":"32","author":"Feldreich","year":"2019","journal-title":"J. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1080\/03009734.2019.1696430","article-title":"Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: A proteomics approach","volume":"125","author":"Carlsson","year":"2020","journal-title":"Upsala J. Med. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12437","DOI":"10.1038\/s41598-021-91772-5","article-title":"Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse","volume":"11","author":"Nguyen","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_23","unstructured":"Andrews, S. (2021, November 27). FastQC: A Quality Control Tool for High Throughput Sequence Data. Available online: http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc."},{"key":"ref_24","unstructured":"Krueger, F. (2019, January 02). Trim Galore!: A Wrapper Tool around Cutadapt and FastQC to Consistently Apply Quality and Adapter Trimming to FastQ Files. Available online: https:\/\/www.bioinformatics.babraham.ac.uk\/projects\/trim_galore\/."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1093\/bioinformatics\/btr167","article-title":"Bismark: A flexible aligner and methylation caller for Bisulfite-Seq applications","volume":"27","author":"Krueger","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1093\/bioinformatics\/bty174","article-title":"A comprehensive evaluation of alignment software for reduced representation bisulfite sequencing data","volume":"34","author":"Sun","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Weinhold, L., Wahl, S., Pechlivanis, S., Hoffmann, P., and Schmid, M. (2016). A statistical model for the analysis of beta values in DNA methylation studies. BMC Bioinform., 17.","DOI":"10.1186\/s12859-016-1347-4"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA Methylation and Its Basic Function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E196","DOI":"10.1152\/ajpendo.00472.2017","article-title":"SRT1720 attenuates obesity and insulin resistance but not liver damage in the offspring due to maternal and postnatal high-fat diet consumption","volume":"315","author":"Nguyen","year":"2018","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/ki.2015.314","article-title":"Increased plasma kidney injury molecule-1 suggests early progressive renal decline in non-proteinuric patients with type 1 diabetes","volume":"89","author":"Nowak","year":"2016","journal-title":"Kidney Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1038\/s41467-019-10378-8","article-title":"Kidney cytosine methylation changes improve renal function decline estimation in patients with diabetic kidney disease","volume":"10","author":"Gluck","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1126\/science.1170116","article-title":"Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1","volume":"324","author":"Tahiliani","year":"2009","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1681\/ASN.2018070736","article-title":"DNA Methyltransferase 1 Controls Nephron Progenitor Cell Renewal and Differentiation","volume":"30","author":"Wanner","year":"2019","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1016\/j.bbadis.2017.05.010","article-title":"DNA methylation regulated gene expression in organ fibrosis","volume":"1863","author":"Zhang","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1146\/annurev-physiol-031620-091656","article-title":"Function of Renal Nerves in Kidney Physiology and Pathophysiology","volume":"83","author":"Osborn","year":"2021","journal-title":"Annu. Rev. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1681\/ASN.2012070678","article-title":"Renal nerves drive interstitial fibrogenesis in obstructive nephropathy","volume":"24","author":"Kim","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1161\/CIRCRESAHA.115.306010","article-title":"Renal denervation prevents immune cell activation and renal inflammation in angiotensin II\u2013induced hypertension","volume":"117","author":"Xiao","year":"2015","journal-title":"Circ. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1093\/ndt\/gfg584","article-title":"Chronic renal denervation prevents glomerular hyperfiltration in diabetic rats","volume":"19","author":"Luippold","year":"2004","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"F251","DOI":"10.1152\/ajprenal.00578.2013","article-title":"Chronic bilateral renal denervation attenuates renal injury in a transgenic rat model of diabetic nephropathy","volume":"307","author":"Yao","year":"2014","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1159\/000500918","article-title":"Catheter-Based Renal Denervation Attenuates Kidney Interstitial Fibrosis in a Canine Model of High-Fat Diet-Induced Hypertension","volume":"44","author":"Gong","year":"2019","journal-title":"Kidney Blood Press. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/bs.pmbts.2017.11.019","article-title":"Wnt Signaling in Kidney Development and Disease","volume":"153","author":"Wang","year":"2018","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1681\/ASN.2008060566","article-title":"Wnt\/\u03b2-Catenin Signaling Promotes Renal Interstitial Fibrosis","volume":"20","author":"He","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s00125-011-2314-2","article-title":"Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy","volume":"55","author":"Zhou","year":"2012","journal-title":"Diabetologia"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"19247","DOI":"10.1038\/s41598-019-55643-4","article-title":"Increased fibroblast growth factor-21 in chronic kidney disease is a trade-off between survival benefit and blood pressure dysregulation","volume":"9","author":"Nakano","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Sugiura, H., Matsushita, A., Futaya, M., Teraoka, A., Akiyama, K.-i., Usui, N., Nagano, N., Nitta, K., and Tsuchiya, K. (2018). Fibroblast growth factor 23 is upregulated in the kidney in a chronic kidney disease rat model. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191706"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fphar.2020.00018","article-title":"Fibroblast Growth Factor 22 Inhibits ER Stress-Induced Apoptosis and Improves Recovery of Spinal Cord Injury","volume":"11","author":"Zhu","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1161\/HYPERTENSIONAHA.120.16247","article-title":"DNA Methylation-Reprogrammed Ang II (Angiotensin II) Type 1 Receptor-Early Growth Response Gene 1-Protein Kinase C \u03b5 Axis Underlies Vascular Hypercontractility in Antenatal Hypoxic Offspring","volume":"77","author":"Xu","year":"2021","journal-title":"Hypertension"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/4\/785\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:18:48Z","timestamp":1760134728000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/4\/785"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,13]]},"references-count":49,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["nu14040785"],"URL":"https:\/\/doi.org\/10.3390\/nu14040785","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,13]]}}}