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An abnormal increase of TGs within cells can lead to intracellular lipid accumulation. In addition to dyslipidemia, hyperglycemia in diabetes may elicit ectopic lipid deposition in non-adipose tissues. Hyperglycemia increases intracellular levels of methylglyoxal (MG) leading to cellular dysfunction. A deficit of glyoxalase I (GLO1) contributes to dicarbonyl stress. Whether dicarbonyl stress induced by MG causes renal lipotoxicity through alteration of lipid metabolism signaling is still unknown. In this study, mice with high fat diet-induced diabetes were used to investigate the renal pathology induced by MG. NRK52E cells treated with MG were further used <jats:italic>in vitro<\/jats:italic> to delineate the involvement of lipogenic signaling. After treatment with MG for 12 weeks, plasma TG levels, renal fatty changes, and tubular injuries were aggravated in diabetic mice. In NRK52E cells, MG activated the nuclear factor erythroid 2-related factor 2 (Nrf2)\/phosphatidylinositol 3-kinase (PI3K)\/protein kinase B (AKT) and sterol regulatory element-binding protein 1 (SREBP1), resulting in stimulation of fatty acid synthase. The intracellular accumulation of lipid droplets was mainly contributed by TGs, which increased the oxidative stress accompanied by high Nrf2 expression. In addition, MG time-dependently activated cyclin D, cyclin-dependent kinase 4 (CDK4), and cleaved caspase-3, evidencing that G<jats:sub>0<\/jats:sub>\/G<jats:sub>1<\/jats:sub> arrest was associated with apoptosis of NRK52E cells. In conclusion, our studies revealed the mechanism of lipotoxicity caused by MG. The target of such dicarbonyl stress may become a promising therapy for diabetic CKD.<\/jats:p>","DOI":"10.1371\/journal.pone.0306575","type":"journal-article","created":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T17:29:57Z","timestamp":1729099797000},"page":"e0306575","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Molecular mechanism of ectopic lipid accumulation induced by methylglyoxal via activation of the NRF2\/PI3K\/AKT pathway implicates renal lipotoxicity caused by diabetes mellitus"],"prefix":"10.1371","volume":"19","author":[{"given":"Chiung Chi","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene Chang Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Rong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charng-Cherng","family":"Chyau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5512-4631","authenticated-orcid":true,"given":"Kuan-Chou","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert Y.","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,10,16]]},"reference":[{"issue":"1","key":"pone.0306575.ref001","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s11154-016-9402-z","article-title":"Dyslipidemia in patients with chronic kidney disease.","volume":"18","author":"MR Hager","year":"2017","journal-title":"Rev Endocr Metab Disord"},{"issue":"7","key":"pone.0306575.ref002","doi-asserted-by":"crossref","DOI":"10.3390\/ijms21072632","article-title":"Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities.","volume":"21","author":"L Opazo-Rios","year":"2020","journal-title":"Int J Mol Sci."},{"issue":"12","key":"pone.0306575.ref003","article-title":"Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study.","volume":"21","author":"YC Lin","year":"2020","journal-title":"Int J Mol Sci."},{"issue":"28","key":"pone.0306575.ref004","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1146\/annurev.nutr.27.061406.093710","article-title":"The Emerging Functions and Mechanisms of Mammalian Fatty Acid\u2013Binding Proteins","volume":"28","author":"J Storch","year":"2008","journal-title":"Annual Review of Nutrition"},{"key":"pone.0306575.ref005","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3389\/fphar.2020.00265","article-title":"Recent Insights Into SREBP as a Direct Mediator of Kidney Fibrosis via Lipid-Independent Pathways.","volume":"11","author":"D Dorotea","year":"2020","journal-title":"Front Pharmacol."},{"issue":"10","key":"pone.0306575.ref006","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1139\/y84-213","article-title":"The lipid content of the diabetic kidney of the rat","volume":"62","author":"G Lemieux","year":"1984","journal-title":"Can J Physiol Pharmacol"},{"issue":"1","key":"pone.0306575.ref007","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0092-8674(94)90234-8","article-title":"SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis","volume":"77","author":"X Wang","year":"1994","journal-title":"Cell"},{"issue":"6","key":"pone.0306575.ref008","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.2337\/db08-0061","article-title":"3rd. 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