Vitamin B12 Modulates Circadian Clock Genes and Protects Early Diabetic Kidney Injury

Vitamin B12 (B12) is a co-factor for methionine synthase and supports DNA/RNA/protein methylation through S-adenosylmethionine production. We previously demonstrated that oral high-dose B12 supplement mitigates diabetic complications in Akita diabetic Elmo1H/H mice, which express twice normal levels of Elmo1 (Engulfment and Cell Motility 1) that enhance diabetic complications. To assess how B12 prevents early stage of kidney damage, we treated nondiabetic and Akita diabetic Elmo1H/H mice with or without B12 in drinking water, starting at 8 weeks old. At 16 weeks, mesangial expansion in untreated diabetic kidneys began, but peritubular fibrosis and inflammatory cell accumulation were minimal. B12-treated diabetic kidneys were essentially normal. RNAseq analysis of the kidneys revealed B12 suppressed expression of genes for adaptive immune response, while upregulated those for solute carrier transporters. Importantly, B12 modulated circadian genes independently of diabetic status: B12 suppressed Clock, Bmal1, and Npas2, while upregulated Cry1/2, Per1–3, Nr1d2, and Dbp. B12 treatment significantly upregulated linker histone H1 variants, suggesting enhanced chromatin stability and transcriptional regulation. In BU.MPT cells, B12 advanced peaks of Bmal1 and Per1, but delayed Cry1, indicating shortened circadian rhythm. As conclusion, B12 supplement effectively mitigates early development of diabetic nephropathy, likely involving regulation of circadian genes and linker H1 regulation.