The Research On TL1A Promoting Inflammation And Apoptosis And Activating NF-κB Pathway To Exacerbate IgA Nephropathy With The Involvement Of Intestinal Mucosal Immunity

Objective:IgA nephropathy（IgAN）is the most common primary glomerular disease around the world,characterized by proliferation of mesangial cells,mesangial hyperplasia and IgA deposition in the mesangial region as the main pathological features,with diverse clinical manifestations.The pathogenesis of IgAN is still unclear,and there are no specific drugs for targeted therapy.Abnormal regulation of mucosal immunity is thought to be an important influence on IgAN and is also involved in the development of inflammatory bowel disease（IBD）,which shares a common genetic background with IgAN.Tumor necrosis factor-like ligand 1A（TL1A）,considered as a core gene involved in mucosal immunity,is a member of tumor necrosis factor superfamily.Current studies on TL1A have focused on immune-related diseases such as inflammatory bowel disease,asthma,and arthritis,where TL1A plays a role in the disease by affecting apoptosis,inflammation,oxidative stress,and fibrosis.IgAN is known as an autoimmune disease,in which TL1A may also play a pathogenic role.In this study,we established a chronic IBD model to explore the pathological changes of mouse kidney in the context of IBD and the role of TL1A in nephropathogenesis and mesangial cell injury and related pathways.Methods:（1）WT mice and TL1A^-/-mice were administrated with dextran sulfate sodium（DSS）to comparatively explore the effects of TL1A in the development of DSS-induced chronic colitis.（2）Investigated the manifestation of IgA nephropathy in mice in the context of colitis and the effects of TL1A on its development.（3）Analyzed the effects of TL1A on renal apoptosis and inflammation by comparing WT mice with TL1A^-/-mice.（4）Incubated mouse mesangial cells using different concentrations of recombinant TL1A protein and comparatively analyzed the effects of different concentrations of TL1A on mesangial cell apoptosis and inflammation.（5）Investigated the mechanism of TL1A in the renal cortex of mice with DSS-induced chronic colitis;and incubated mouse renal mesangial cells for different time points with recombinant TL1A protein to explore the mechanism of TL1A regulation on mesangial cells.Results:（1）The weight change and pathology score of TL1A^-/-mice were lower than those of WT mice when the mice were administrated with DSS;and the colons were longer than those of WT mice（P<0.05）.（2）The glomeruli of WT mice showed more IgA deposition and higher mesangial proliferation than those of TL1A^-/-mice.（3）In the context of chronic colitis,the relative expression of Bax,i NOS and Cox-2increased in WT mice,as well as serum IL-6;and the corresponding indexes decreased in TL1A^-/-mice（P<0.05）.（4）After incubating mouse mesangial cells with different concentrations of recombinant TL1A protein,high concentration of TL1A significantly promoted apoptosis and the expression of inflammatory mediators like i NOS,Cox-2 and IL-6（P<0.05）.（5）The expression of p-I?Bαand p-P65 protein in the kidney cortex of TL1A^-/-mice was significantly reduced compared with WT mice in the context of chronic colitis（P<0.05）;using recombinant TL1A protein to incubate mouse mesangial cells for different time points,the expression of p-I?Bαand p-P65 significantly increased after 30 min of incubation;and these suggested that TL1A could activate the NF-κB pathway for further action.Conclusion:（1）IgA deposition and pathological changes were found in the kidney of DSS-induced chronic colitis mice;TL1A deletion attenuated the corresponding manifestations.（2）TL1A caused mesangial cell injury by mediating inflammatory mediator production and apoptosis.（3）TL1A aggravated mesangial cell injury by activating NF-κB pathway.