Glomerular Haematopoietic Prostaglandin D Synthase-Prostaglandin D2 Axis Contributes to the Periodontitis-Related Exacerbation of Diabetic Nephropathy in KK-Ay Mice

Diabetic nephropathy (DN) is the leading cause of dialysis and is associated with cardiovascular diseases. To prevent the progression of DN, not only glycemic control but also intervention to exacerbating factors such as chronic inflammation and infection. Recent clinical studies have shown the possible association between chronic kidney disease including DN, and periodontitis. However, the causal relationship that periodontitis could contribute to the progression of DN and its molecular mechanisms has not been understood. In the present study, we investigated ligature-induced experimental periodontitis that might exacerbate glomerular pathology in a DN model KK-Ay mice and the underlying molecular mechanisms. KK-Ay mice with experimental periodontitis showed significantly increased urinary albumin to creatinine ratio, and glomerular pathologies such as glomerular size, mesangial expansion area, fibrotic area, and number of CD68-positive leukocytes compared to those without ligatures. RNA-sequencing in the glomeruli revealed that hematopoietic prostaglandin d2 synthase (Hpgds) was the possible factor bridging periodontitis with the progression of DN. We also found that Hpgds expression was significantly upregulated by hyperglycemia and inflammatory stimuli in mesangial cells. Prostaglandin D2 enhanced hyperglycemia-induced collagen expression in mesangial cells and downregulated the tight junction in renal endothelial cells. Lastly, oral administration with an HPGDS inhibitor HQL-79 successfully prevented the progression of DN in KK-Ay mice by experimental periodontitis. Taken together, experimental periodontitis might contribute to the progression of DN via acceleration of glomerular pathology by upregulation of HPGDS in mesangial cells. Overall design: Male KK-Ay and C57 BL/6 mice at 13 weeks old were placed 6-0 silk ligatures around the maxillary second molars for 3 weeks. 16 weeks old mice were sacrificed to isolate glomeruli fractions from their kidneys and RNA were extracted from them using RNA extraction kit (PureLink). We then performed RNA-seq using glomerular RNA from C57BL/6, C57BL/6 with experimental periodontitis, KK-Ay, and KK-Ay with experimental periodontitis. Comparative gene expression analysis among 4 groups were performed.