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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE261386 | GEO | 2025/05/03

REPOSITORIES: GEO

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Project description:Validation of predicted gene expression of human mesangial cells after 24h Tacrolimus stimulus Objective: To evaluate tacrolimus as therapeutic option for diabetic nephropathy (DN) based on molecular profile and network-based molecular model comparisons. Materials and Methods: We generated molecular models representing pathophysiological mechanisms of DN and tacrolimus mechanism of action (MoA) based on literature derived data and transcriptomics datasets. Shared enriched molecular pathways were identified based on both model datasets. A newly generated transcriptomics dataset studying the effect of tacrolimus on mesangial cells in vitro was added to identify mechanisms in DN pathophysiology. We searched for features in interference between the DN molecular model and the tacrolimus MoA molecular model already holding annotation evidence as diagnostic or prognostic biomarker in the context of DN. Results: Thirty nine molecular features were shared between the DN molecular model, holding 252 molecular features and the tacrolimus MoA molecular model, holding 209 molecular features, with six additional molecular features affected by tacrolimus in mesangial cells. Significantly affected molecular pathways by both molecular model sets included cytokine-cytokine receptor interactions, adherens junctions, TGF-beta signaling, MAPK signaling, and calcium signaling. Molecular features involved in inflammation and immune response contributing to DN progression were significantly downregulated by tacrolimus (e.g. the tumor necrosis factor alpha (TNF), interleukin 4, or interleukin 10). On the other hand, pro-fibrotic stimuli being detrimental to renal function were induced by tacrolimus like the transforming growth factor beta 1 (TGFB1), endothelin 1 (EDN1), or type IV collagen alpha 1 (COL4A1). Conclusion: Patients with DN and elevated TNF levels might benefit from tacrolimus treatment regarding maintaining GFR and reducing inflammation. TGFB1 and EDN1 are proposed as monitoring markers to assess degree of renal damage. Next to this stratification approach, the use of drug combinations consisting of tacrolimus in addition to ACE inhibitors, angiotensin receptor blockers, TGFB1- or EDN1-receptor antagonists might warrant further studies. comparison of gene expression of human mesangial cells after 24h Tacrolimus vs. Ctrl; 4 independent experiments were conducted (4xTacrolimus 24h and 4x ctrl. 24h with Drug solvent (DMSO))

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

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