Diabetic nephropathy (DN) is the major cause of kidney related diseases in patients induced by high
glucose (HG) affecting around 40% of type 1 and 2 diabetic patients. It is characterized by excessive
inflammation inducing factors,
reactive oxygen species (ROS) overproduction, and potential epigenomic related changes.
Fucoxanthin (FX), a
carotenoid found in brown seaweed, has a structure which includes an allenic bond and a 5,6-monoepoxide in the molecule, with strong
antioxidant and anti-inflammatory activity. However, understanding of the impact of FX on DN was lacking. In this study we tested the early effects of high
glucose (HG) on mouse mesangial kidney Mes13 cells, a potential in vitro cell culture model of DN. Our results show that HG induced oxidative stress on kidney mesangial Mes13 cells, while FX treatment attenuates the oxidative stress by decreasing the ROS, demonstrated by flow cytometry. Next, we utilized next-generation sequencing (NGS) to profile the HG-induced early epigenomic and transcriptomic changes in this in vitro DN model and the protective effects of FX. Differentially expressed genes (DEGs) and differentially methylated regions (DMRs) were analyzed using R software in HG and FX treated groups. Differential regulation of signaling pathways was studied using Reactome Pathway Analysis in the comparison. DEG analysis shows that novel
biomarkers with specific pathways, including
interleukin regulation,
Toll-like receptor pathway, and PKA phosphorylation pathways, were found to be modulated by the FX treatment. TGF β 1i1 (TGFB 1i1), MAP-3-kinase-13(MAP3K13) involved in crucial cellular processes including
glucose metabolism,
phosphodiesterase regulation was methylated in HG, which was demethylated with FX treatment. Integrated transcriptomic and CpG methylome analysis of DEGs and DMRs revealed that genes like
adenylate cyclase (Adcy7),
calponin 1 (CNN1),
potassium voltage-gated channel interacting
protein 2 (KCNIP2),
phosphatidylinositol-4-phosphate 5-kinase type 1 β (PIP5K1B), and transmembrane
protein with
EGF-like and two
follistatin-like domains 1 (TMEFF1), which were modulated by FX in HG-exposed Mes13 cells, potentially modulate
ion channel transport and
glucose metabolism. In summary, our current study shows that novel early epigenomic and transcriptomic
biomarkers were altered during the
disease progression of HG-induced DN and that FX modified these alterations potentially contributing to the protective effects of mesangial cells from the HG-induced oxidative stress and damage.