Porphyromonas gingivalis Induces Chronic Kidney Disease through Crosstalk between the NF-κB/NLRP3 Pathway and Ferroptosis in GMCs

Objective Porphyromonas gingivalis(P.gingivalis)is a gram-negative bacterium found in the human oral cavity and is a recognized pathogenic bacterium associated with chronic periodontitis and systemic diseases,including chronic kidney disease(CKD),but the roles and molecular mechanism of P.gingivalis in CKD pathogenesis are unclear.Methods In this study,an animal model of oral P.gingivalis administration and glomerular mesangial cells(GMCs)cocultured with M1-polarized macrophages and P.gingivalis supernatant were constructed.After seven weeks of P.gingivalis gavaged,peripheral blood was collected to detect the changes in renal function.By collecting the teeth and kidneys of mice,H&E staining and IHC were used to analyze the expression of periodontal inflammatory factors in mice,PAS staining was used to analyze glomerular lesions.The supernatant of macrophages was treated with 5%P.gingivalis supernatant.H&E staining,IHC,Western blot and RT-PCR were applied to analyze renal inflammatory factors,macrophage M1 polarization,NF-κB,NLRP3 and ferroptosis changes in vitro.Results We found that oral P.gingivalis administration induced CKD in mice.P.gingivalis supernatant induced macrophage polarization and inflammatory factor upregulation,which triggered the activation of the NF-κB/NLRP3 pathway and ferroptosis in GMCs.By inhibiting the NF-κB/NLRP3 pathway and ferroptosis in GMCs,cell viability and the inflammatory response were partially alleviated in vitro.Conclusion We demonstrated that P.gingivalis induced CKD in mice by triggering crosstalk between the NFκB/NLRP3 pathway and ferroptosis in GMCs.Overall,our study suggested that periodontitis can promote the pathogenesis of CKD in mice,which provides evidence of the importance of periodontitis therapy in the prevention and treatment of CKD.