Long-term arsenic exposure causes epithelial-mesenchymal transition and kidney fibrosis accompanied by renal lipid metabolic disorders.

Chronic kidney disease (CKD) represents one of the global public health challenges. Several epidemiological reports indicate that environmental arsenic exposure is associated with CKD. This study aimed to investigate the effect of long-term arsenic exposure on renal lipid metabolism during the development of kidney fibrosis. Adult C57BL/6 mice were administered NaAsO2 (3 or 15 mg/L) in drinking water for 6 months. Urinary protein, NGAL, α1-MG and β2-MG, markers of tubular injury, were increased in arsenic-exposed mice. In the later stage, renal inflammation and epithelial-mesenchymal transition indicators remained elevated. Collagen genes, including Col1a1, Col1a2, Col11a1, and Col11a2, were upregulated and collagen deposition was aggravated in the kidneys of arsenic-exposed mice. Mechanistically, renal lipid composition, as assessed by lipidomics, was significantly altered in arsenic-exposed mice. In the later stage, renal free fatty acids (FFAs) remained increased. Renal triglyceride (TG) content was elevated, and lipid droplet deposition was observed. Transcriptome sequencing showed that fatty acid oxidation (FAO) pathways were enriched in arsenic-exposed mouse kidneys. Real-time RT-PCR found that renal FAO-related genes were downregulated in arsenic-exposed mice. These results indicate that long-term arsenic exposure induces kidney fibrosis accompanied by renal lipid droplet deposition. Renal lipid metabolic disorders might be a mediating mechanism underlying arsenic-induced kidney fibrosis.