Sodium Butyrate Attenuates Renal Fibrosis by Regulating Glycolysis and Histone H4K12 Lactylation in Diabetic Kidney Disease.

BACKGROUND

The role of histone lactylation in diabetes associated renal fibrosis remains poorly defined. In this study, we investigated the contribution of histone H4 lysine 12 lactylation (H4K12la) to abnormal glycolysis and renal fibrogenesis in diabetic kidney disease (DKD) and evaluated sodium butyrate (NaB) as a potential therapeutic modulator.

METHODS

In this study, db/db mice (Bks. Cg-leprdb/leprdb) were employed as an in vivo model of DKD, and high glucose-treated human tubular epithelial cells (HK-2 cells) were used as an in vitro model to investigate whether NaB exerts protective effects on DKD via modulating glycolysis and histone H4K12 lactylation-mediated hypoxia-inducible factor-1α (HIF-1α) activation.

RESULTS

We found that H4K12la expression was significantly increased in diabetic kidneys, which was closely associated with enhanced glycolysis related fibrosis. Analysis of kidney biopsy tissues from patients with DKD confirmed that H4K12la levels were significantly elevated. CUT&Tag sequencing in HK-2 cells revealed enrichment of H4K12la at genes involved in metabolic pathways, including the promoter region of HIF1A. In vivo and in vitro experiments demonstrated that NaB treatment suppressed the expression of glycolytic enzymes hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA), reduced lactate production, improved renal function, and attenuated kidney fibrosis under diabetic conditions. Mechanistically, these effects were associated with decreased H4K12la enrichment at the HIF1A promoter.

CONCLUSIONS

Collectively, our findings identify aberrant renal glycolysis and H4K12la as key drivers of diabetic renal fibrosis and suggest that NaB mitigates fibrosis by modulating glycolysis-dependent H4K12la and HIF-1α signalling.