The Pathogenesis Of Pulmonary Oxidative Stress In Idiopathic Membranous Nephropathy

BackgroundMembranous nephropathy(MN)is a common pathological type of adult nephrotic syndrome,which is characterized by the deposition of immune complexes in the glomerular subepicthelial space.The clinical manifestations are proteinuria and edema.Idiopathic membranous nephropathy(IMN)of unknown etiology accounted for 70%80%.The latest data show that the incidence of IMN is increasing,which has doubled compared with 10 years ago.Therefore,exploring the etiology and pathogenesis of IMN has been a research hotspot in the field of kidney disease.It is known that M--type phospholipase A2 receptor(PLA2R)is the most common target antigen of adult IMN,and its specific antibody(aPLA2Rab)is a marker for the occurrence,development and prognosis of IMN.The mechanism of PLA2R antibody production is unknown,and it is currently believed to be caused by autoimmune activation induced by PLA2R epitope exposure.Basic research has confirmed that oxidative stress is a key factor inducing PLA2R epitope exposure.Clinical studies have found that air fine particulate matter and smoking are closely related to the occurrence and development of IMN,while PM2.5 and smoking can cause inflammation and oxidative stress damage in lung tissue.Therefore,this study intends to explore the pathogenic role of pulmonary oxidative stress in IMN and its possible mechanism from the perspective of lung-kidney interaction.Methods1.Patients with IMN confirmed by renal biopsy in our hospital were selected.Serum PLA2R antibody and oxidative stress indicators such as CAT,SOD and MDA were detected,and the expression of serum exosomal PLA2R was analyzed.2.Lung tissues of patients who underwent lobectomy for lung cancer in our hospital were collected.The patients were divided into smoking group and nonsmoking group.The co-localization of PLA2R and SOD2 in lung tissue with alveolar epithelial cells was detected,and the expression of PLA2R in lung tissue exosomes was analyzed.3.Lipopolysaccharide(LPS)was used to stimulate lung epithelial cells in vitro to explore the effect of oxidative stress on the expression of PLA2R in lung epithelial cells.Results1.In IMN patients,the serum oxidative stress index MDA was positively correlated with the level of PLA2R antibody and 24h urine protein,while SOD was negatively correlated with the level of PLA2R antibody.2.Compared with the non-smoking group,the expression of PLA2R in lung tissue of the smoking group was significantly enhanced,and both PLA2R and SOD2 were co-localized with alveolar type II epithelial cells.3.LPS stimulation of lung epithelial cells can lead to the up-regulation of PLA2R expression,and GSH can inhibit the up-regulation of PLA2R caused by LPS.4.Immunoelectron microscopy and nano-flow cytometry confirmed the presence of PLA2R+exosomes in the serum of IMN patients.Statistics showed that the proportion of PLA2R+exosomes was positively correlated with serum PLA2R antibody level.5.The expression of pulmonary exosomal PLA2R was increased in the smoking group,and the macrophage marker CD206 was highly expressed in the exosomes.Conclusion1.Serum oxidative stress indicators and PLA2R+exosomes in IMN patients are closely related to the degree of IMN disease.2.The expression of PLA2R and SOD2 in alveolar type II epithelial cells of smokers is up-regulated.In vitro experiments,LPS stimulation of pulmonary epithelial cells leads to oxidative stress and PLA2R expression enhancement,suggesting that pulmonary oxidative stress is the initial factor of PLA2R epitope exposure.3.Lung tissue of smokers can secrete PLA2R+ exosomes,suggesting that lung tissue-derived PLA2R+ exosomes are immunogenic,which may lead to the production of PLA2R antibody and participate in the pathogenesis of IMN.