Periodontitis-Aggravated Diabetic Kidney Disease with Altered Glycolysis

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, and its progression is influenced by metabolic and inflammatory factors beyond hyperglycemia. Periodontitis, a common chronic inflammatory disease, has been associated with adverse renal outcomes in diabetes, but the underlying mechanisms remain unclear. The objective of this study is to evaluate the impact of experimental periodontitis (EP) on DKD progression and its association with renal glycolytic alterations. EP was induced in male db/db mice using silk ligation combined with Porphyromonas gingivalis administration. Renal function, histopathology, inflammatory responses, and glycolytic metabolism were assessed in vivo. Transcriptomic datasets were integrated for pathway analysis, and in vitro experiments were performed in human proximal tubular epithelial (HK-2) cells. EP significantly exacerbated kidney dysfunction and renal fibrosis in diabetic mice without further increasing fasting blood glucose levels. These changes were accompanied by enhanced epithelial–mesenchymal transition (EMT) activation in renal tubular cells. Diabetic kidneys exhibited increased expression of glycolytic-related enzymes and lactate accumulation and decreased adenosine triphosphate levels and NAD + /NADH ratios; these alterations were further aggravated by EP. Bioinformatic analysis revealed enrichment of EMT- and mTORC1-related pathways in DKD with periodontitis. Pharmacologic inhibition of mammalian target of rapamycin (mTOR) partially attenuated EP-associated renal dysfunction, fibrosis, partial EMT, and glycolytic alterations. In HK2 cells, tumor necrosis factor–α amplified high-glucose–induced (mTOR)/hypoxia-inducible factor-1α (HIF-1α) activation, glycolysis, and EMT; these alterations were attenuated by rapamycin or HIF-1α silencing. Together, these findings suggest that periodontitis is associated with aggravated DKD through altered glycolysis, partial EMT, and fibrosis. The mTOR/HIF-1α axis may represent a linking pathway between periodontal inflammation and metabolic and phenotypic alterations in renal tubular cells.