Academic Journal
Folate Deficiency Drives Metabolic Dysfunction, Oxidative Stress, and Inflammation in HK-2 Renal Tubular Cells.
| Τίτλος: | Folate Deficiency Drives Metabolic Dysfunction, Oxidative Stress, and Inflammation in HK-2 Renal Tubular Cells. |
|---|---|
| Συγγραφείς: | Chiu TI; Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan., Liu HY; Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan., Lin BF; Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan. |
| Πηγή: | International journal of molecular sciences [Int J Mol Sci] 2026 Oct 03; Vol. 27 (19). Date of Electronic Publication: 2026 Oct 03. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Basel, Switzerland : MDPI, [2000- |
| Ιατρικοί όροι (MeSH): | Inflammation*/metabolism , Inflammation*/pathology , Kidney Tubules*/metabolism , Kidney Tubules*/pathology , Folic Acid Deficiency*/metabolism , Folic Acid Deficiency*/pathology , Folic Acid Deficiency*/complications , Oxidative Stress*, NF-kappa B/metabolism ; Mitochondria/metabolism ; Chemokine CCL2/metabolism ; Interleukin-6/metabolism ; Reactive Oxygen Species/metabolism ; Fructose/metabolism ; Epithelial Cells/metabolism ; Lactic Acid/metabolism ; L-Lactate Dehydrogenase/metabolism ; Folic Acid/metabolism ; Humans ; Cell Line ; Lipopolysaccharides |
| Περίληψη: | The growing aging population has been accompanied by an increasing prevalence of chronic kidney disease (CKD), highlighting the need to better understand modifiable dietary and metabolic factors that contribute to renal injury. Folate deficiency and excessive fructose intake have been implicated in renal inflammation; however, the underlying cellular mechanisms remain incompletely understood. In this study, we investigated the effects of folate deficiency or fructose exposure on inflammatory responses, lactate metabolism, oxidative stress, and mitochondrial function in human renal tubular epithelial HK-2 cells. Folate deficiency markedly increased the secretion of the pro-inflammatory cytokines interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), accompanied by enhanced NF-κB activation, both in the presence and absence of lipopolysaccharide (LPS) stimulation. Notably, folate-deficient cells exhibited increased lactate dehydrogenase (LDH) activity, intracellular lactate accumulation, and lactate secretion. Exogenous lactate supplementation or modulation of lactate production using the LDH inhibitor oxamate further demonstrated that elevated lactate promoted IL-6 and transforming growth factor-β1 (TGF-β1) production, NF-κB activation, and reactive oxygen species (ROS) generation. Consistent with these findings, folate deficiency significantly reduced the oxygen consumption ratio (OCR), indicating impaired mitochondrial function and a metabolic shift away from oxidative phosphorylation toward increased lactate production. High fructose exposure also enhanced IL-6 and MCP-1 secretion, particularly following LPS stimulation, while both LPS exposure and folate deficiency further increased lactate production. Collectively, these findings identify lactate accumulation as a potential metabolic link between folate deficiency, inflammation, oxidative stress and fibrotic signaling in renal tubular HK-2 cells. This metabolic-inflammatory pathway may contribute to the initiation and progression of CKD and highlights folate status and lactate metabolism as potential targets for preventing diet-associated renal injury. |
| References: | Exp Ther Med. 2022 Jul 01;24(3):552. (PMID: 35978931) J Biomed Sci. 2009 Jul 14;16:64. (PMID: 19594948) Cell Prolif. 2025 Sep;58(9):e70034. (PMID: 40207870) Nat Rev Nephrol. 2025 Jan;21(1):39-56. (PMID: 39289568) Int J Mol Sci. 2025 Mar 27;26(7):. (PMID: 40243751) Am J Physiol Renal Physiol. 2019 Jun 1;316(6):F1162-F1172. (PMID: 30969803) J Anim Sci Biotechnol. 2025 May 1;16(1):62. (PMID: 40307878) J Nutr Biochem. 2017 Mar;41:65-72. (PMID: 28040582) Open Med (Wars). 2021 Aug 26;16(1):1256-1264. (PMID: 34514170) Oxid Med Cell Longev. 2020 Jan 23;2020:5478708. (PMID: 32082479) Aging (Albany NY). 2021 Apr 4;13(7):10326-10353. (PMID: 33819919) Nutrients. 2023 Aug 17;15(16):. (PMID: 37630806) Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11715-20. (PMID: 9751731) Clin J Am Soc Nephrol. 2019 Oct 7;14(10):1441-1449. (PMID: 31551237) Front Mol Biosci. 2022 Jan 12;8:806650. (PMID: 35096971) Chin Med J (Engl). 2017 May 20;130(10):1236-1243. (PMID: 28485325) Life Sci. 2023 Apr 15;319:121432. (PMID: 36706833) Redox Biol. 2025 Sep;85:103754. (PMID: 40663910) Mol Cancer. 2009 Jun 05;8:32. (PMID: 19497135) Mol Cell. 2023 Nov 2;83(21):3904-3920.e7. (PMID: 37879334) Redox Biol. 2024 Sep;75:103246. (PMID: 38925041) Dis Markers. 2019 Oct 7;2019:1814304. (PMID: 31687048) Lancet. 2021 Oct 2;398(10307):1199-1201. (PMID: 34562392) Immun Ageing. 2024 Dec 27;21(1):88. (PMID: 39731136) Cells. 2025 May 28;14(11):. (PMID: 40497970) Antioxidants (Basel). 2025 May 29;14(6):. (PMID: 40563291) JAMA Intern Med. 2016 Oct 01;176(10):1443-1450. (PMID: 27548766) EClinicalMedicine. 2023 Dec 12;67:102366. (PMID: 38169713) Cell Metab. 2011 Jan 5;13(1):11-22. (PMID: 21195345) Cells. 2022 Dec 25;12(1):. (PMID: 36611880) Br J Nutr. 2024 Oct 14;132(7):898-918. (PMID: 39411832) Kidney Int. 2024 Aug;106(2):226-240. (PMID: 38789037) Cell Metab. 2026 Jun 2;38(6):1130-1140.e6. (PMID: 41881014) Clin Exp Nephrol. 2026 Jun;30(6):905-913. (PMID: 41984139) Br J Nutr. 2007 May;97(5):855-63. (PMID: 17381984) Clin J Am Soc Nephrol. 2014 Nov 7;9(11):1868-75. (PMID: 25359387) Curr Opin Toxicol. 2018 Feb;7:81-86. (PMID: 29862377) Mol Cell Biochem. 2000 Mar;206(1-2):105-12. (PMID: 10839200) Evid Based Complement Alternat Med. 2011;2011:254531. (PMID: 19745004) Physiology (Bethesda). 2015 May;30(3):183-94. (PMID: 25933819) Am J Clin Nutr. 2022 Aug 4;116(2):599-607. (PMID: 35460222) Nutrients. 2026 Mar 13;18(6):. (PMID: 41901086) Kidney Int. 2024 Aug;106(2):183-185. (PMID: 39032962) Clin J Am Soc Nephrol. 2017 Feb 7;12(2):272-279. (PMID: 27932391) Br J Nutr. 2010 Apr;103(8):1195-204. (PMID: 19968891) Cell Death Dis. 2019 Sep 10;10(9):653. (PMID: 31506428) Signal Transduct Target Ther. 2021 Jun 28;6(1):242. (PMID: 34176927) Front Nutr. 2022 Apr 25;9:852451. (PMID: 35548560) J Ethnopharmacol. 2010 May 27;129(2):244-9. (PMID: 20371279) |
| Grant Information: | NSTC 112-2320-B-002-030-MY2 National Science and Technology Council |
| Contributed Indexing: | Keywords: chronic kidney disease; folate; inflammation; lactate; lactate dehydrogenase; oxidative stress |
| Substance Nomenclature: | 0 (NF-kappa B) 0 (Chemokine CCL2) 0 (Interleukin-6) 0 (Reactive Oxygen Species) 30237-26-4 (Fructose) 0 (Lipopolysaccharides) 33X04XA5AT (Lactic Acid) EC 1.1.1.27 (L-Lactate Dehydrogenase) 0 (CCL2 protein, human) 935E97BOY8 (Folic Acid) |
| Entry Date(s): | Date Created: 20261016 Date Completed: 20261016 Latest Revision: 20261020 |
| Update Code: | 20261020 |
| PubMed Central ID: | PMC13665185 |
| DOI: | 10.3390/ijms27198846 |
| PMID: | 42884089 |
| Βάση Δεδομένων: | MEDLINE |
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