Folate Deficiency Drives Metabolic Dysfunction, Oxidative Stress, and Inflammation in HK-2 Renal Tubular Cells
- 1Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan
Abstract
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.
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BibTeX
@article{chiu2026folate,
title = {{Folate Deficiency Drives Metabolic Dysfunction, Oxidative Stress, and Inflammation in HK-2 Renal Tubular Cells}},
author = {Te-I Chiu and Hsiang-Yu Liu and Bi-Fong Lin},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27198846},
url = {https://www.mdpi.com/1422-0067/27/19/8846},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Folate Deficiency Drives Metabolic Dysfunction, Oxidative Stress, and Inflammation in HK-2 Renal Tubular Cells
AU - Te-I Chiu
AU - Hsiang-Yu Liu
AU - Bi-Fong Lin
PY - 2026
DA - 2026/10/03
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27198846
UR - https://www.mdpi.com/1422-0067/27/19/8846
AB - 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.
SN - 1422-0067
ER -