Mechanism of Histone H4K12 Lactylation Regulating AKR1B1 Promoting Kidney Injury in Diabetes and Treatment Effect of Fecal Microbiota Transplantation

Background: The aim of this study was to investigate the role and molecular mechanism of histone H4K12 lactylation in DKD; to clarify the regulation of acyltransferase P300 on the H4K12la/AKR1B1 pathway; and to investigate whether FMT can inhibit H4K12la levels and reduce diabetic kidney injury by decreasing the production of the gut microbiota metabolite lactate. To provide new targets and strategies for the treatment of DKD Methods: Detected the non-targeted metabolome in urine of healthy people and DKD patients. The contents of lactic acid in serum and renal tissue of control and diabetic mice were detected, and the expression levels of Pan-Kla and H4K12la in renal tissue were detected by western blot and immunohistochemical experiments. The expression levels of P300, H4K12la and AKR1B1 were detected by western blot, and the expression and localization of H4K12la were detected by immunofluorescence.Pseudo-sterile mouse models were obtained by intragastric administration of antibiotic suspension to db/db mice for 1 week, subsequently, the fecal suspension of healthy mice was gavaged for 10 weeks to obtain the FMT treatment group; bifidobacterium was gavaged to obtain the Bifi treatment group. Results: In the DKD state, lactate production and H4K12la levels are up-regulated in a lactate concentration-dependent manner. Inhibition of H4K12la reduces mitochondrial dysfunction and abnormal fatty acid metabolism, lipid accumulation, inflammatory factors and extracellular matrix secretion in HK-2 cells cultured in high glucose. In diabetic mouse models, FMT exerts renoprotective effects by regulating gut microbiota composition, decreasing serum differential metabolite lactate content, inhibiting H4K12la/AKR1B1/STAT3 levels, reducing mitochondrial dysfunction and abnormal fatty acid metabolism, and reducing lipid accumulation, inflammation, and fibrosis levels. In diabetic mouse models, bifidobacteria exerts renoprotective effects by regulating gut microbiota composition , promoting serum differential metabolite butyrate production, and up-regulating PPARγ/ LXRα/ABCA1 axis expression, promoting cholesterol efflux, and reducing lipid accumulation, inflammation, and fibrosis levels. Conclusion: Histone H4K12 lactylation regulating AKR1B1 promoting renal injury in diabetes and Fecal Microbiota Transplantation have treatment effect.