Efficacy and safety of Mahuang Fuzi and Shenzhuo Decoction for treatment of primary membranous nephropathy: a multicenter prospective trial.

BACKGROUND: This study aims to undertake a comprehensive assessment of the effectiveness and safety profile of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in the management of primary membranous nephropathy (PMN), within the context of a prospective clinical investigation. METHODS: A multicenter, open-label clinical trial was executed on patients diagnosed with PMN. These individuals were subjected to MFSD therapy for a duration of at least 24 months, with primary outcome of clinical remission rates. The Cox regression analysis was employed to discern the pertinent risk factors exerting influence on the efficacy of MFSD treatment, with scrupulous monitoring of any adverse events. RESULTS: The study comprised 198 participants in total. Following 24 months of treatment, the remission rate was 58.6% (116/198). Among the subgroup of 130 participants subjected to a 36-month follow-up, the remission rate reached 70% (91/130). Subgroup analysis revealed that neither a history of immunosuppressive therapy (HIST) nor an age threshold of ≥60 years exhibited a statistically significant impact on the remission rate at the 24-month mark (p > .05). Multivariate Cox regression analyses elucidated HIST, nephrotic syndrome, or mass proteinuria, and a high-risk classification as noteworthy risk factors in the context of MFSD treatment. Remarkably, no fatalities resulting from side effects were documented throughout the study's duration. CONCLUSIONS: This trial establishes the efficacy of MFSD as a treatment modality for membranous nephropathy. MFSD demonstrates a favorable side effect profile, and remission rates are consistent across patients, irrespective of HIST and age categories.

Integrating network pharmacology and experimental validation to decipher the mechanism of the Chinese herbal prescription modified Shen-Yan-Fang-Shuai formula in treating diabetic nephropathy.

CONTEXT: Diabetic nephropathy (DN) is the main cause of end-stage renal disease. Modified Shen-Yan-Fang-Shuai formula (M-SYFSF) has excellent clinical efficacy in treating diabetic kidney disease. However, the potential mechanism of M-SYFSF remains unknown. OBJECTIVE: To investigate the mechanism of M-SYFSF against DN by network pharmacological analysis and biological experiments. MATERIALS AND METHODS: Utilizing a web-based pharmacology database, the potential mechanisms of M-SYFSF against DN were identified. In vivo experiments, male SD rats were injected with streptozotocin (50 mg/kg) and got uninephrectomy to construct a model of DN. M-SYFSF (11.34 g/kg/d) was gavaged once per day for 12 weeks after model establishment. In vitro experiments, human proximal tubular cells (HK-2) were performed with advanced glycation end-products (AGEs) (100 µg/mL), then intervened with M-SYFSF freeze-dried powder. Pathological staining, WB, IHC, ELISA were conducted to explore the mechanism of M-SYFSF against DN. RESULTS: Network pharmacological analysis showed that MAPK pathway was the potential pathway. Results showed that compared with the Model group, M-SYFSF significantly reduced 24h urine albumin, UACR, and serum creatinine levels (54.90 ± 26.67 vs. 111.78 ± 4.28, 8.87 ± 1.69 vs. 53.94 ± 16.01, 11.56 ± 1.70 vs. 118.70 ± 49.57, respectively), and improved renal pathological changes. Furthermore, the intervention of M-SYFSF reduced the expression of pro-inflammatory cytokines and inhibited the activation of MAPK pathway in AGEs-treated HK-2 cells. DISCUSSION AND CONCLUSION: M-SYFSF is likely to reduce inflammation in DN by inhibiting the MAPK pathway. It provides a theoretical basis for the clinical application of M-SYFSF in the treatment of DN.

Corrigendum: MicroRNAs: Potential mediators between particulate matter 2.5 and Th17/Treg immune disorder in primary membranous nephropathy.

[This corrects the article DOI: 10.3389/fphar.2022.968256.].

Cytokines network in primary membranous nephropathy.

There have been extensive studies on the immunological mechanism of primary membranous nephropathy (PMN). Autoantibodies, being the end product of humoral auto-immunity, matter much in diagnosis, therapy and prediction. Although PMN has been thought of as oligoinflammatory glomerulopathy, autoimmune diseases usually involve inflammation and it may be long-lasting. Cytokines are key mediators and effector molecules of inflammatory and humoral immune responses. Their function and network are helpful to understand the immune mechanism of PMN, but there is a lack of systematic summary. Accordingly, this review explores the advance of cytokines in PMN, and clarifies whether inflammation involves in the pathological process of PMN, based on which certain cytokines are proposed as potential biomarkers or therapeutic targets, and the importance of updating existing therapy regimens is highlighted.

MicroRNAs: Potential mediators between particulate matter 2.5 and Th17/Treg immune disorder in primary membranous nephropathy.

Primary membranous nephropathy (PMN), is an autoimmune glomerular disease and the main reason of nephrotic syndrome in adults. Studies have confirmed that the incidence of PMN increases yearly and is related to fine air pollutants particulate matter 2.5 (PM2.5) exposure. These imply that PM2.5 may be associated with exposure to PMN-specific autoantigens, such as the M-type receptor for secretory phospholipase A2 (PLA2R1). Emerging evidence indicates that Th17/Treg turns to imbalance under PM2.5 exposure, but the molecular mechanism of this process in PMN has not been elucidated. As an important indicator of immune activity in multiple diseases, Th17/Treg immune balance is sensitive to antigens and cellular microenvironment changes. These immune pathways play an essential role in the disease progression of PMN. Also, microRNAs (miRNAs) are susceptible to external environmental stimulation and play link role between the environment and immunity. The contribution of PM2.5 to PMN may induce Th17/Treg imbalance through miRNAs and then produce epigenetic affection. We summarize the pathways by which PM2.5 interferes with Th17/Treg immune balance and attempt to explore the intermediary roles of miRNAs, with a particular focus on the changes in PMN. Meanwhile, the mechanism of PM2.5 promoting PLA2R1 exposure is discussed. This review aims to clarify the potential mechanism of PM2.5 on the pathogenesis and progression of PMN and provide new insights for the prevention and treatment of the disease.

Identification of molecular mechanism and key biomarkers in membranous nephropathy by bioinformatics analysis.

OBJECTIVES: Membranous nephropathy (MN) is an autoimmune nephropathy. The incidence of MN is increasing gradually in recent years. Previous studies focused on antibody production, complement activation and podocyte injury in MN. However, the etiology and underlying mechanism of MN remain to be further studied. METHODS: GSE104948 and GSE108109 of glomerular expression profile were downloaded from Gene Expression Omnibus (GEO) database, GSE47184, GSE99325, GSE104954, GSE108112, GSE133288 of renal tubule expression profile, and GSE73953 of peripheral blood mononuclear cells (PBMCs) expression profile. After data integration by Networkanalyst, differentially expressed genes (DEGs) between MN and healthy samples were obtained. DEGs were enriched in gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG), and protein-protein interaction (PPI) networks of these genes were constructed through Metascape, etc. We further understood the function of hub genes through gene set enrichment analysis (GSEA). The diagnostic value of DEGs in MN was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: A total of 3 genes (TP53, HDAC5, and SLC2A3) were screened out. Among them, the up-regulated TP53 expression may be closely related to MN renal pathological changes. However, the expression of MN podocyte target antigen was not significantly different from that of healthy controls. In addition, the changes of Wnt signaling pathway in PBMCs and the effects of SLC2A3 on the differentiation of M2 monocyte need further study. CONCLUSION: It is difficult to unify a specific mechanism for the changes of glomerulus, renal tubules and PBMCs in MN patients. This may be related to the pathogenesis, pathology and immune characteristics of MN. MN podocyte target antigen may not be the root cause of the disease, but a stage result in the pathogenesis process.

Level of interleukin-35 in patients with idiopathic membranous nephropathy and its predictive value for remission time.

Objective: As a member of interleukin-12 family, interleukin-35 (IL-35) plays an important regulatory role in immune response. The relationship between IL-35 and idiopathic membranous nephropathy (IMN) is still unclear, and the purpose of this study is to clarify the relationship between IL-35 and disease activity and remission of IMN. Methods: This study was a single-center, retrospective study in which all patients were diagnosed with IMN by renal biopsy or aPLA2R titer and treated with Mahuang Fuzi and Shenzhuo Decoction (MFSD). A follow-up was conducted with the endpoint of clinical complete or partial remission (CR+PR). Levels of serum IL-35 were measured and its relationship with IMN remission were analyzed. The regulatory T cell (Treg) and inducible IL-35 producing Tregs (iTR35) in peripheral blood of IMN patients were detected by flow cytometry. Results: A total of 76 IMN patients (age 51.95 ± 13.29) were followed-up for 18 (12, 24) months. The level of serum IL-35 in all patients increased after treatment, but the degree of increase in remission group was significantly higher than that in no remission (NR) group (117.6% vs 83.7%, P<0.01). The baseline IL-35 level in remission group was higher than that in NR group (174.87 vs.151.87 pg/ml, P=0.016). Cox regression analysis showed that baseline IL-35 level was a independent risk factor for IMN remission (HR 1.081, 95%CI 1.048-1.116, P<0.001). Patients with baseline IL-35 lower than the lower quartile (≤145.49 pg/ml) had an average remission time twice as long as those with baseline IL-35 higher than the upper quartile (> 203.05 pg/ml) (12mon vs. 24mon, P<0.01). The baseline IL-35 can predict the remission time of IMN patients with either aPLA2R positive (AUC=0.673) or negative (AUC=0.745). Analysis of 18 patients with IMN showed that IL-35 level had a higher correlation with iTR35, but not Treg (r=0.613, P<0.05). Conclusions: The level of IL-35 in patients with IMN showed an increasing trend with the progress of treatment, and the baseline IL-35 could predict the remission time of IMN patients, including those patients with negative aPLA2R. The level of IL-35 is related to the number of iTR35 cells.

The Ameliorative Effect of Mahuang Fuzi and Shenzhuo Decoction on Membranous Nephropathy of Rodent Model is Associated With Autophagy and Wnt/ß-Catenin Pathway.

The increased incidence of membranous nephropathy (MN) has made it the most common pathological type of primary nephrotic syndrome in adults in China. According to the theory of Traditional Chinese Medicine (TCM), Mahuang Fuzi (Chinese ephedra and Radix Aconiti Lateralis Preparata) and Shenzhuo Decoction (MFSD) could be used to treat such diseases. We treated patients of MN with MFSD, and observed comparable efficacy to glucocorticoid and/or immunosuppressants. In this study, we observed the therapeutic effect of MFSD on the rat model of passive Heymann nephritis (PHN), a classical MN model. Our results showed that MFSD treatment significantly reduced urinary protein level and podocyte injury in PHN rats, and correspondingly improved renal pathology, with the improvement effect on MN comparable to that of Cyclosporine A (CsA) alone. To explore the potential therapeutical mechanism of MFSD, the main chemical components of MFSD were determined by High-performance liquid chromatography-mass spectrometry (HPLC-MS). There were about 30 active components of MFSD. Next, based on network pharmacology methods, we screened related targets of MSFD on MN, which provided a preliminary understanding of the MFSD bioactive compounds. The clustering analysis showed that its active site might be in the autophagy-related protein and Wnt/ß-catenin pathway, which was related to podocyte injury. Finally, we observed an improvement in renal autophagy and a down-regulation of the Wnt/ß-catenin pathway after MSFD treatment in a PHN rat model. According to this study, autophagy and Wnt/ß-catenin pathway may be potential targets for MFSD in the treatment of MN.

Effect of Mahuang Fuzi and Shenzhuo Decoction on Idiopathic Membranous Nephropathy: A Multicenter, Nonrandomized, Single-Arm Clinical Trial.

Objective: To explore the clinical effect of Mahuang Fuzi and Shenzhuo Decoction on idiopathic membranous nephropathy. Methods: This study is a multicenter, nonrandomized, single-arm clinical trial carried out as per the objective performance criteria, with the target being set at 35.0%. 184 cases of patients suffering from idiopathic membranous nephropathy with Shaoyin Taiyin syndrome were collected. These patients were treated with Mahuang Fuzi and Shenzhuo Decoction with a follow-up period of 3 years. The 24-hour urine protein and blood albumin were observed, and the remission rates of the patients were compared with the target. Results: The mean follow-up time was 18 (12.5, 30) months, and the remission rate was 61.4%, which is a statistically significant difference from the target group of 35%. The remission rates for patients who had and had not used immunosuppressive therapy were 59.6 and 65.5%, respectively, but the difference was not statistically significant (p = 0.254). However, the albumin before the treatment and the course of treatment of the patients was significantly correlated with the disease remission (p < 0.05). However, the albumin before the treatment and the course of treatment of the patients was significantly correlated with the disease remission (p < 0.05). There were no significant changes in renal function before and after treatment, and no severe adverse events occurred during treatment. Conclusion: Mahuang Fuzi and Shenzhuo Decoction have significant effects on idiopathic membranous nephropathy, and has the same effect on patients with membranous nephropathy who are newly treated as well as those who have been treated with immunosuppressive therapy without remission. In addition, the efficacy of this regimen is related to the albumin and the duration of the therapy, but not to 24-hour urine protein or other factors.

A Novel Insight into the Role of PLA2R and THSD7A in Membranous Nephropathy.

Membranous nephropathy (MN) is an organ-restricted autoimmune disease mainly caused by circulating autoantibodies against podocyte antigens, including the M-type phospholipase A2 receptor (PLA2R) and thrombospondin domain-containing 7A (THSD7A). Antibodies against PLA2R are present in 70%-80% and against THSD7A in 2% of adult patients, which provides a paradigm shift in molecular diagnosis and management monitoring. Both antigens share some similar characteristics: they are expressed by podocytes and have wide tissue distributions; they are bound by autoantibodies only under nonreducing conditions, and the subtype of most autoantibodies is IgG4. However, the factors triggering autoantibody production as well as the association among air pollution, malignancy, and the pathogenesis of MN remain unclear. In this review, we discuss the similarity between the pathological mechanisms triggered by disparate antigens and their associated diseases. Furthermore, we demonstrated the possibility that PM2.5, malignancy, and gene expression specifically induce exposure of these antigens through conformational changes, molecular mimicry, or increased expression eliciting autoimmune responses. Thus, this review provides novel insights into the pathological mechanism of MN.

Helper T Cells in Idiopathic Membranous Nephropathy.

Idiopathic membranous nephropathy (IMN) is an autoimmune disease in which the immune system produces an antibody response to its own antigens due to impaired immune tolerance. Although antibodies are derived from plasma cells differentiated by B cells, the T-B cells also contribute a lot to the immune system. In particular, the subsets of helper T (Th) cells, including the dominant subsets such as Th2, Th17, and follicular helper T (Tfh) cells and the inferior subsets such as regulatory T (Treg) cells, shape the immune imbalance of IMN and promote the incidence and development of autoimmune responses. After reviewing the physiological knowledge of various subpopulations of Th cells and combining the existing studies on Th cells in IMN, the role model of Th cells in IMN was explained in this review. Finally, the existing clinical treatment regimens for IMN were reviewed, and the importance of the therapy for Th cells was highlighted.

Inhibition of the Wnt/ß-catenin signaling pathway reduces autophagy levels in complement treated podocytes.

In idiopathic membranous nephropathy, the complement membrane attack complex, more commonly referred to as complement 5b-9 (C5b-9), induces glomerular epithelial cell injury and proteinuria. C5b-9 can also activate numerous mechanisms that restrict or facilitate injury. Recent studies suggest that autophagy and the canonical Wnt signaling pathway serve an important role in repairing podocyte injury. However, the effect of C5b-9 on these pathways and the relationship between them remains unclear. The aim of the present study was to show the effect of C5b-9 on the Wnt/ß-catenin signaling pathway and autophagy in podocytes in vitro. Levels of relevant indicators were detected by immunofluorescence staining and capillary western immunoassay. C5b-9 serum significantly activated the Wnt/ß-catenin signaling pathway and promoted autophagy. Treatment with Dickkopf-related protein 1 (DKK1), a Wnt/ß-catenin pathway blocker, protected podocytes from injury and significantly inhibited autophagy. The results indicated that inhibition of the Wnt/ß-catenin pathway physiologically activated autophagy. The results indicated that C5b-9 resulted in a decrease in Akt in podocytes. However, the podocytes preincubated with DKK1 and then attacked by C5b-9 showed an increase in Akt levels. This may explain the observation that blocking the Wnt/ß-catenin signaling pathway attenuated C5b-9 podocyte damage, while inhibiting autophagy. The results of the present study also suggest that regulation of these two pathways may serve as a novel method for the treatment of idiopathic membranous nephropathy.

Mechanism of herbal medicine on hypertensive nephropathy (Review).

Hypertensive nephropathy is the most common complication of hypertension, and is one of the main causes of end­stage renal disease (ESRD) in numerous countries. The basic pathological feature of hypertensive nephropathy is arteriolosclerosis followed by renal parenchymal damage. The etiology of this disease is complex, and its pathogenesis is mainly associated with renal hemodynamic changes and vascular remodeling. Despite the increased knowledge on the pathogenesis of hypertensive nephropathy, the current clinical treatment methods are still not effective in preventing the development of the disease to ESRD. Herbal medicine, which is used to relieve symptoms, can improve hypertensive nephropathy through multiple targets. Since there are few clinical studies on the treatment of hypertensive nephropathy with herbal medicine, this article aims to review the progress on the basic research on the treatment of hypertensive nephropathy with herbal medicine, including regulation of the renin angiotensin system, inhibition of sympathetic excitation, antioxidant stress and anti­inflammatory protection of endothelial cells, and improvement of obesity­associated factors. Herbal medicine with different components plays a synergistic and multi­target role in the treatment of hypertensive nephropathy. The description of the mechanism of herbal medicine in the treatment of hypertensive nephropathy will contribute towards the progress of modern medicine.

Exploring the Differences in Molecular Mechanisms and Key Biomarkers Between Membranous Nephropathy and Lupus Nephritis Using Integrated Bioinformatics Analysis.

Background: Both membranous nephropathy (MN) and lupus nephritis (LN) are autoimmune kidney disease. In recent years, with the deepening of research, some similarities have been found in the pathogenesis of these two diseases. However, the mechanism of their interrelationship is not clear. The purpose of this study was to investigate the differences in molecular mechanisms and key biomarkers between MN and LN. Method: The expression profiles of GSE99325, GSE99339, GSE104948 and GSE104954 were downloaded from GEO database, and the differentially expressed genes (DEGs) of MN and LN samples were obtained. We used Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for enrichment analysis of DEGs. A protein-protein interaction (PPI) network of DEGs was constructed using Metascape. We filtered DEGs with NetworkAnalyst. Finally, we used receiver operating characteristic (ROC) analysis to identify the most significant DEGs for MN and LN. Result: Compared with LN in the glomerulus, 14 DEGs were up-regulated and 77 DEGs were down-regulated in MN. Compared with LN in renal tubules, 21 DEGs were down-regulated, but no up-regulated genes were found in MN. According to the result of GO and KEGG enrichment, PPI network and Networkanalyst, we screened out six genes (IFI6, MX1, XAF1, HERC6, IFI44L, IFI44). Interestingly, among PLA2R, THSD7A and NELL1, which are the target antigens of podocyte in MN, the expression level of NELL1 in MN glomerulus is significantly higher than that of LN, while there is no significant difference in the expression level of PLA2R and THSD7A. Conclusion: Our study provides new insights into the pathogenesis of MN and LN by analyzing the differences in gene expression levels between MN and LN kidney samples, and is expected to be used to prepare an animal model of MN that is more similar to human.

Idiopathic Membranous Nephropathy: Glomerular Pathological Pattern Caused by Extrarenal Immunity Activity.

Idiopathic membranous nephropathy (IMN) is a pathological pattern of glomerular damage caused by an autoimmune response. Immune complex deposition, thickness of glomerular basement membrane, and changes in the podocyte morphology are responsible for the development of proteinuria, which is caused by the targeted binding of auto-antibodies to podocytes. Several auto-antigens have recently been identified in IMN, including M-type receptor for secretory phospholipase A2 (PLA2R1), thrombospondin type-1 domain-containing 7A (THSD7A), and neural epidermal growth factor-like 1 protein (NELL-1). The measurement of peripheral circulating antibodies has become an important clinical reference index. However, some clinical features of IMN remain elusive and need to be further investigated, such as the autoimmunity initiation, IgG4 predominance, spontaneous remission, and the unique glomerular lesion. As these unresolved issues are closely related to clinical practice, we have proposed a hypothetical pathogenesis model of IMN. Induced by environmental stimuli or other causes, the PLA2R1 antigen and/or THSD7A antigen exposed to extrarenal tissues, such as lungs, then produce the auto-antibodies that target and cause damage to the podocytes in circulation. In this review, we highlighted the potential association between environmental stimuli, immune activity, and glomerular lesions, the underlying basis for spontaneous immune and proteinuria remission.

Alleviation by Mahuang Fuzi and Shenzhuo Decoction in High Glucose-Induced Podocyte Injury by Inhibiting the Activation of Wnt/ß-Catenin Signaling Pathway, Resulting in Activation of Podocyte Autophagy.

BACKGROUND: Organ fibrosis is a common endpoint of a variety of diseases. Many studies have shown that the pathogenesis of diabetic kidney disease (DKD) is related to the excessive activation of the Wnt/ß-catenin signaling pathway on podocytes, so the treatment of DKD starts from this signaling pathway. At the same time, DKD, as a metabolic disease, has many connections related to podocyte autophagy. OBJECTIVES: We experimented the effects of Mahuang Fuzi and Shenzhuo decoction (MFSD) which is the combination of Mahuang Fuzi decoction and Shenzhuo decoction in traditional Chinese medicine compounds used "The Golden Chamber" in high glucose-induced podocytes, determined whether this effect was related to Wnt/ß-catenin signaling pathway, and further investigated the relationship between this effect and autophagy. METHODS: The mice podocytes were stimulated by using 30 mmol/L of high glucose and serum containing MFSD or Wnt/ß-catenin signaling pathway inhibitor DKK1 (100 ng/ml) was used to intervene podocytes before high glucose stimulation. Podocyte injury-related proteins, Wnt/ß-catenin signaling pathway-related proteins, and autophagy-related proteins were detected by using western blotting and immunofluorescence analysis. RESULTS: Our results showed that DKK1 and MFSD treatment significantly upregulated the protein expressions of nephrin, podocin, podocalyxin, and podoplanin in high glucose-induced podocytes and downregulated the ß-catenin protein expression. Furthermore, the protein expressions of beclin1, LC3B, and P62 were also significantly increased in high glucose-induced podocytes. CONCLUSION: Our experiments confirmed that the destruction of podocytes in DKD is related to the excessive activation of Wnt/ß-catenin signaling pathway and the inhibition of autophagy after activation. MFSD treatment can inhibit the activation of Wnt/ß-catenin signaling pathway in podocytes stimulated by high glucose and helpful in reducing the podocyte injury. This protective mechanism can be related to the enhancement of podocyte autophagy by MFSD treatment.

How Does Herbal Medicine Treat Idiopathic Membranous Nephropathy?

Idiopathic membranous nephropathy (IMN) has made increasing progress in mechanism and treatment research. Herbal medicine is gradually being accepted as an alternative therapy in treating IMN. However, the intervention mechanism of herbal medicine in the treatment of membranous nephropathy is still unclear. In this review, we summarize some achievements of herb medicine in treating IMN and discuss the research direction of herb in IMN. Finally, we propose the dilemma about the study on the treatment of IMN with herb medicine. We hope that this article can bring some thoughts for clinical and scientific researchers on the treatment of IMN with herb medicine.

The Potential Role of Regulatory B Cells in Idiopathic Membranous Nephropathy.

Regulatory B cells (Breg) are widely regarded as immunomodulatory cells which play an immunosuppressive role. Breg inhibits pathological autoimmune response by secreting interleukin-10 (IL-10), transforming growth factor-ß (TGF-ß), and adenosine and through other ways to prevent T cells and other immune cells from expanding. Recent studies have shown that different inflammatory environments induce different types of Breg cells, and these different Breg cells have different functions. For example, Br1 cells can secrete IgG4 to block autoantigens. Idiopathic membranous nephropathy (IMN) is an autoimmune disease in which the humoral immune response is dominant and the cellular immune response is impaired. However, only a handful of studies have been done on the role of Bregs in this regard. In this review, we provide a brief overview of the types and functions of Breg found in human body, as well as the abnormal pathological and immunological phenomena in IMN, and propose the hypothesis that Breg is activated in IMN patients and the proportion of Br1 can be increased. Our review aims at highlighting the correlation between Breg and IMN and proposes potential mechanisms, which can provide a new direction for the discovery of the pathogenesis of IMN, thus providing a new strategy for the prevention and early treatment of IMN.

Immunological Pathogenesis of Membranous Nephropathy: Focus on PLA2R1 and Its Role.

Membranous nephropathy (MN) is the major cause of nephrotic syndrome with special pathological features, caused by the formation of immune complexes in the space between podocytes and the glomerular basement membrane. In idiopathic membranous nephropathy (IMN) the immune complexes are formed by circulating antibodies binding mainly to one of two naturally-expressed podocyte antigens: the M-type receptor for secretory phospholipase A2 (PLA2R1) and the Thrombospondin type-1 domain-containing 7A (THSD7A). Formation of antibodies against PLA2R1 is much more common, accounting for 70-80% of IMN. However, the mechanism of anti-podocyte antibody production in IMN is still unclear. In this review, we emphasize that the exposure of PLA2R1 is critical for triggering the pathogenesis of PLA2R1-associated MN, and propose the potential association between inflammation, pollution and PLA2R1. Our review aims to clarify the current research of these precipitating factors in a way that may suggest future directions for discovering the pathogenesis of MN, leading to additional therapeutic targets and strategies for the prevention and early treatment of MN.