Vitamin D is involved in the effects of the intestinal flora and its related metabolite TMAO on perirenal fat and kidneys in mice with DKD

BACKGROUND: Vitamin D was shown to directly exert a protective effect on diabetic kidney disease (DKD) in our previous study. However, whether it has an effect on perirenal adipose tissue (PRAT) or the intestinal flora and its metabolites (trimethylamine N-oxide, TMAO) is unclear. METHODS: DKD mice received different concentrations of 1,25-(OH)2D3 for 2 weeks. Serum TNF-α and TMAO were measured. 16S rRNA sequencing profiled gut microbiota. qPCR assessed TLR4, NF-κB, PGC1α, and UCP-1 expression in kidney and adipose tissue. Kidney and PRAT histology was evaluated by HE, PAS, Masson and Oil Red O staining; immunofluorescence and immunohistochemistry detected VDR, PGC1α, podocin, and UCP-1; electron microscopy examined renal ultrastructure. VDR knockout mice were generated to assess gut and adipose changes and renal UCP-1 and collagen IV. RESULTS: 1,25-(OH)2D3 improved intestinal dysbiosis in DKD mice, increased beneficial bacteria and decreased harmful bacteria, reduced renal pathology and fat infiltration, and downregulated renal TLR4 and NF-κB. Serum TMAO was significantly elevated in DKD versus controls and positively correlated with urine ACR. Vitamin D increased PGC1α, UCP-1, and VDR expression in PRAT; TMAO downregulated PRAT and renal VDR. CONCLUSIONS: The protective effect of 1,25-(OH)2D3 in DKD mice may involve modulation of intestinal flora and its metabolite TMAO, influencing PRAT and kidney.

Xiaodi Zheng, Yuhong Huang, Mengxue Yang, Lulu Jin, Xuemeng Zhang, Rui Zhang, Yueyue Wu, Cuili Yan, Yuan Gao, Miao Zeng, Fei Li, Xue Zhou, Neng Zhang, Jun Liu, Bingbing Zha