The Role Of C5a/C5aR Axis Activation Mediated By Factor P In Podocyte Injury Of IgA Nephropathy

IgA nephropathy(IgA nephropathy,IgAN)is an autoimmune disease mediated by pathogenic immune complexes,and is a common primary glomerular disease that causes end-stage renal disease(ESRD).There are currently few reports on the pathogenesis of IgA nephropathy podocyte damage.Previous studies have suggested that poly-IgAl molecules are deposited in the mesangial area and cause podocyte damage through the "mesangial-podocyte interaction".Transforming growth factor-β(TGF-β)and angiotensin Ⅱ(Angiotensin Ⅱ,Ang-Ⅱ)are the main mediators of mesangial-podocyte interaction,which promote the expression of tumor necrosis factor-a(TNF-α)and its receptors in podocytes,leading to The fusion of podocyte foot processes produces proteinuria,podocyte apoptosis,dedifferentiation and loss of adhesion,which eventually leads to podocyte shedding and progressive glomerulosclerosis.It is clinically found that some patients with IgA nephropathy with a large amount of proteinuria have only mild mesangial hyperplasia,and under the electron microscope,it is found that the podocytes of this part of the patients have diffuse foot process fusion,showing that the local podocytes are de-adhesive,and the degree of podocyte damage is related to The proliferation of mesangial cells is not consistent,suggesting that the interaction between mesangial cells and podocytes is not the only mechanism of podocyte damage in IgA nephropathy.The study of the mechanism of complement activation in podocyte injury is currently focused on the molecular pathways related to the membrane attack complex C5b-9.A sufficient dose of C5b-9 as perforin can directly damage the podocytes,and a sub-dose of C5b-9 can Stimulate podocytes to release protein kinases,oxidants and cytokines,and induce apoptosis of podocytes.The role of C5a,another important effector product of complement activation,in podocyte injury is poorly understood.C5a is a key effect product of complement activation.It plays a role by combining with C5aR.Recently,more and more studies have focused on C5a’s involvement in the pathogenesis of a variety of primary kidney diseases.Complement is activated by three pathways:Classic Pathway(CP),Alternative Pathway(AP)and Mannose binding lectin(MBL)pathway.Complement activation in IgA nephropathy is mainly through the alternative pathway and mannose.Combined with the lectin pathway.Previous studies have found that 75%-100%of patients with IgA nephropathy have factor P deposition on the kidney tissue.Factor P is a positive regulator of complement activation,but in IgA nephropathy podocyte injury,how factor P activates and regulates complement needs further research.This study will lay the foundation for revealing the pathogenesis of podocyte damage in IgA nephropathy from the new perspective that C5a/C5aR axis activation mediated by factor P in the alternative pathway of complement,and also open up new ideas for the clinical treatment of massive proteinuria in IgA nephropathy.ObjectiveTo explore the role of C5a/C5aR axis activation mediated by alternative complement pathway factor P of podocyte injury in IgA nephropathy.MethodsA total of 60 patients with different degrees of proteinuria and IgA nephropathy in our hospital(24-hour urine protein quantification of 0-1 g,1-3.5g,and>3.5g)were selected as the case group,and 20 kidney donors who underwent renal biopsy at zero point As a normal control group,enzyme-linked immunosorbent assay(ELISA)was used to detect the activation of the alternative complement pathway in plasma and urine to positively regulate the level of factor P.(2)Observe the degree of podocyte damage in patients with IgA nephropathy in each group by electron microscope,and use terminal transferase labeling technique(TUNEL)to count podocyte apoptosis.(3)Immunofluorescence detection of Nephrin expression in IgA nephropathy podocytes,laser confocal detection:① Nephrin and factor P expression on IgA nephropathy podocytes,② Nephrin and C5aR expression on IgA nephropathy podocytes,③Nephrin and C5b-9 in IgA nephropathy Expression on podocytes.Results(1)Nephrin expression in renal tissues of patients with massive proteinuria and IgA nephropathy decreased,podocyte foot processes diffusely merged,and podocyte apoptosis increased significantly.(2)Confocal laser showed that the expression of factor P,C5aR and C5b-9 on the podocytes of patients with massive proteinuria and IgA nephropathy was significantly increased,and the expression of Nephrin was weakened.(3)Compared with the normal control group,the serum factor P level of patients with IgA nephropathy was significantly higher(P=0.049),and it was positively correlated with 24-hour urine protein quantification(r=0.426,P=0.001),but there was no statistically significant relationship with serum creatinine(P=0.190),the level of urine factor P/urinary creatinine in patients with IgA nephropathy was higher than that in the normal control group(P=0.001),and it was related to 24-hour urine protein quantification(r=0.395,P=0.003)and serum creatinine(r=0.409,P=0.002)are all positively correlated.ConclutionThe excessive activation of C5a/C5aR axis mediated by factor P in the alternative pathway of complement may be involved in the occurrence of podocyte injury in IgA nephropathy.The severity of IgA nephropathy is related to the activation level of the alternative pathway of complement.