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

ABSTRACT Aims Recent clinical studies have proposed a potential association between chronic kidney diseases, including diabetic nephropathy (DN) and periodontitis. Nevertheless, the causal relationship of periodontitis with DN and the underlying molecular mechanisms remain unclear. Materials and Methods Ligature‐induced experimental periodontitis (LIP) was induced in KK‐A y mice to investigate the molecular mechanisms underlying the LIP‐mediated aggravation of glomerular pathology in DN. Outpatients with type 2 diabetes (T2D) at Kyushu University Hospital were recruited to confirm the association of renal dysfunction and periodontitis with a urinary factor identified by RNA sequencing (RNA‐seq) in the mouse glomeruli. Results LIP aggravated renal dysfunction and glomerular pathologies in KK‐A y mice. RNA‐seq in the glomeruli revealed haematopoietic prostaglandin D synthase (HPGDS) as the possible factor bridging periodontitis with DN progression. Glomerular PGD2 levels in KK‐Ay mice were significantly elevated by LIP. Oral administration of an HPGDS inhibitor, HQL‐79, successfully prevented LIP‐mediated DN progression in KK‐A y mice by lowering glomerular PGD2 levels. Urinary HPGDS‐to‐creatinine ratio could be associated with renal dysfunction and periodontitis in outpatients with T2D. Conclusion Periodontitis may contribute to DN progression via the glomerular HPGDS–PGD2 axis. These results suggest a novel mechanism in periodontitis‐related DN progression.