OBJECTIVETo highlight current knowledge about M-type phospholipase A2 receptor (PLA2R) which is the first human autoantigen discovered in adult idiopathic membranous nephropathy.

DATA SOURCESRelevant articles published in English from 2000 to present were selected from PubMed. Searches were made using the terms "idiopathic membranous nephropathy, M-type PLA2R and podocyte."

STUDY SELECTIONArticles studying the role of M-type PLA2R in idiopathic membranous nephropathy were reviewed. Articles focusing on the discovery, detection and clinical observation of anti-PLA2R antibodies were selected.

RESULTSM-type PLA2R is a member of the mannose receptor family of proteins, locating on normal human glomeruli as a transmembrane receptor. The anti-PLA2R in serum samples from MN were primarily IgG4 subclass. Technologies applied to detect anti-PLA2R autoantibody are mainly WB, IIFT, ELISA and so on. Studies from domestic and overseas have identified a strongly relationship between circulating anti-PLA2R levels and disease activity.

CONCLUSIONRecent discoveries corresponding to PLA2R facilitate a better understanding on IMN pathogenesis and may provide a new tool to its diagnosis, differential diagnosis, risk evaluation, response monitoring and patient-specific treatment.

Animals ; Autoantigens ; metabolism ; Glomerulonephritis, Membranous ; immunology ; metabolism ; Humans ; Podocytes ; metabolism ; Receptors, Phospholipase A2 ; metabolism

Objective To investigate the clinical significance of thrombospondin type 1 domain-containing 7A (THSD7A) and neural epidermal growth factor-like 1 protein (NELL1) in phospholipase A2 receptor (PLA2R)-negative membranous nephropathy (MN). Methods A total of 116 PLA2R-negative MN patients treated in Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University from 2014 to 2021 were enrolled in this study.Immunohistochemistry was employed to detect THSD7A and NELL1 in the renal tissue.The pathological characteristics,treatment,and prognosis were compared between positive and negative groups. Results The 116 PLA2R-negative MN patients included 23 THSD7A-positive patients and 9 NELL1-positive patients.One patient was tested positive for both proteins.The THSD7A-positive group showed higher positive rate of IgG4 (P=0.010),more obvious glomerular basement membrane (GBM) thickening (P=0.034),and higher proportion of stage Ⅱ MN and lower proportion of stage I MN (P=0.002) than the THSD7A-negative group.The NELL1-positive group had lower positive rates of C1q and IgG2 (P=0.029,P=0.001),less obvious GBM thickening (P<0.001),more extensive inflammatory cell infiltration (P=0.033),lower proportion of deposits on multi-locations (P=0.001),and lower proportion of atypical MN (P=0.010) than the NELL1-negative group.One patient with THSD7A-positive MN was diagnosed with colon cancer,while none of the NELL1-positive patients had malignancy.Survival analysis suggested that THSD7A-positive MN had worse composite remission (either complete remission or partial remission) of nephrotic syndrome than the negative group (P=0.016),whereas NELL1-positive MN exhibited better composite remission of nephrotic syndrome than the negative group (P=0.015).The MN patients only positive for NELL1 showed better composite remission of nephrotic syndrome than the MN patients only positive for THSD7A (P<0.001). Conclusions THSD7A- and NELL1-positive MN is more likely to be primary MN,and there is no significant malignancy indication.However,it might have a predictive value for the prognosis of MN.
Humans ; Autoantibodies ; Clinical Relevance ; Colonic Neoplasms ; EGF Family of Proteins ; Glomerulonephritis, Membranous/diagnosis* ; Nephrotic Syndrome ; Receptors, Phospholipase A2/metabolism* ; Thrombospondins/metabolism*

OBJECTIVETo investigate the prevalence of PLA2R1 in renal biopsy specimens of patients with idiopathic membranous nephropathy (IMN) and explore the relationship between PLA2R1 and IMN.

METHODSA total of 108 adult patients with biopsy-proved glomerular diseases were enrolled in this study, including 41 with IMN, 2 with hepatitis B-associated membranous nephropathy, 8 with V lupus nephritis, 27 with IgA nephropathy, 19 with minimal change nephropathy, 5 with mild mesangial proliferative glomerulonephritis, and 6 with focal segmental glomeruloselerosis (FSGS). Indirect immunofluorescence assay was used to detect PLA2R1 in the biopsy specimens and the clinical variables of the IMN patients were analyzed.

RESULTSIn 35 of the 41 (85.37%) patients with IMN, PLA2R1 was detected with a fine granular pattern in the subepithelial deposits along the glomerular capillary loops. PLA2R1 antigen was not detected in patients with other glomerulopathies. No significant differences were found in age, serum creatinine, serum albumin, or 24-h urinary protein level between PLA2R1-positive and negative patients with IMN (P>0.05).

CONCLUSIONAccording to our results, 85.37% of adult patients with biopsy-proven IMN are positive for PLA2R1 antigen, which, however, does not contribute to variations of the patients' clinical manifestations.

Adult ; Biopsy ; Glomerulonephritis, Membranous ; metabolism ; Humans ; Kidney ; metabolism ; pathology ; Kidney Function Tests ; Kidney Glomerulus ; pathology ; Nephrosis, Lipoid ; metabolism ; Receptors, Phospholipase A2 ; metabolism

BACKGROUNDAccording to the renal phospholipase A2 receptor (PLA2R) immunohistochemistry, idiopathic membranous nephropathy (iMN) could be categorized into PLA2R-associated and non-PLA2R-associated iMN. This study aimed to examine whether the non-PLA2R-associated iMN had any difference in clinical features compared with PLA2R-associated iMN.

METHODSA total of 231 adult patients diagnosed as iMN were recruited to this retrospective study. Renal PLA2R expression was examined by immunofluorescence. Among these patients, 186 (80.5%) with complete baseline clinical data were used for further study. Urinary protein excretion, serum albumin, and creatinine were analyzed. For those patients with follow-up longer than 1 year, the relationship between PLA2R and response to immunosuppressants were analyzed. The t-test was used for parametric analysis and the Mann-Whitney U-test was used for nonparametric analysis. Categorical variables were described as frequencies or percentages, and the data were analyzed with Pearson's Chi-square test or Fisher's exact test.

RESULTSOf the 231 iMN patients, 189 showed renal detectable PLA2R expression (81.8%). The baseline serum creatinine, serum albumin, and urine protein excretion were not significantly different between PLA2R-associated (n = 145) and non-PLA2R-associated iMN patients (n = 41). However, about 1/3 of the non-PLA2R-associated iMN had abnormal serological tests, significantly more common than PLA2R-associated iMN (31.7% vs. 8.3%, P = 0.000). The non-PLA2R-associated iMN had lower C4 levels compared with PLA2R-associated iMN (P = 0.004). The non-PLA2R-associated iMN patients also showed a better response to immunosuppressants (complete remission [CR] 42.9%; partial remission [PR] 14.3%) compared with PLA2R-associated iMN (CR 3.2%; PR 48.4%, P = 0.004) at the 3rd month.

CONCLUSIONSThere were no significant differences in serum creatinine, albumin, and urine protein excretion between PLA2R-associated and non-PLA2R-associated iMN, while the non-PLA2R-associated iMN patients showed more abnormal serological tests. The non-PLA2R-associated iMN seemed to respond more quickly to the immunosuppressive therapy compared with PLA2R-associated iMN.

Adult ; Autoantibodies ; metabolism ; Female ; Glomerulonephritis, Membranous ; drug therapy ; metabolism ; pathology ; urine ; Humans ; Immunosuppressive Agents ; therapeutic use ; Kidney ; metabolism ; pathology ; Male ; Middle Aged ; Receptors, Phospholipase A2 ; metabolism ; Retrospective Studies

Angiopoietin-like 4 Protein ; Angiopoietins ; analysis ; blood ; urine ; Antibodies ; analysis ; blood ; urine ; Disease Progression ; Glomerulonephritis, Membranous ; diagnosis ; metabolism ; Humans ; Receptors, Phospholipase A2 ; immunology

Adult ; Female ; Gene Expression ; Glomerulonephritis, Membranous ; etiology ; genetics ; pathology ; Hepatitis B ; complications ; Hepatitis B virus ; genetics ; metabolism ; Humans ; Male ; Middle Aged ; Mutation ; Receptors, Phospholipase A2 ; genetics ; metabolism ; Trans-Activators ; genetics ; metabolism ; Viral Regulatory and Accessory Proteins ; genetics ; metabolism

Contraction of smooth muscle is initiated by an increase in cytosolic Ca2+ leading to activation of Ca2+/calmodulin-dependnet myosin light chain (MLC) kinase and phosphorylation of MLC. The types of contraction and signaling mechanisms mediating contraction differ depending on the region. The involvement of these different mechanisms varies depending on the source of Ca2+ and the kinetic of Ca2+ mobilization. Ca2+ mobilizing agonists stimulate different phospholipases (PLC-beta, PLD and PLA2) to generate one or more Ca2+ mobilizing messengers (IP3 and AA), and diacylglycerol (DAG), an activator of protein kinase C (PKC). The relative contributions of PLC-beta, PLA2 and PLD to generate second messengers vary greatly between cells and types of contraction. In smooth muscle cell derived form the circular muscle layer of the intestine, preferential hydrolysis of PIP2 and generation of IP3 and IP3-dependent Ca2+ release initiate the contraction. In smooth muscle cells derived from longitudinal muscle layer of the intestine, preferential hydrolysis of PC by PLA2, generation of AA and AA-mediated Ca2+ influx, cADP ribose formation and Ca2+/-induced Ca2+ release initiate the contraction. Sustained contraction, however, in both cell types is mediated by Ca2+/-independent mechanism involving activation of PKC- epsilon by DAG derived form PLD. A functional linkage between G13, RhoA, ROCK, PKC- epsilon, CPI-17 and MLC phosphorylation in sustained contraction has been implicated. Contraction of normal esophageal circular muscle (ESO) in response to acetylcholine (ACh) is linked to M2 muscarinic receptors activating at least three intracellular phospholipases, i.e. phosphatidylcholine-specific phospholipase C (PC-PLC), phospholipase D (PLD) and the high molecular weight (85 kDa) cytosolic phospholipase A2 (cPLA2) to induce phosphatidylcholine (PC) metabolism, production of diacylglycerol (DAG) and arachidonic acid (AA), resulting in activation of a protein kinase C (PKC)-dependent pathway. In contrast, lower esophageal sphincter (LES) contraction induced by maximally effective doses of ACh is mediated by muscarinic M3 receptors, linked to pertussis toxin-insensitive GTP-binding proteins of the Gq/11 type. They activate phospholipase C, which hydrolyzes phosphatidylinositol bisphosphate (PIP2), producing inositol 1, 4, 5-trisphosphate (IP3) and DAG. IP3 causes release of intracellular Ca2+ and formation of a Ca2+/-calmodulin complex, resulting in activation of myosin light chain kinase and contraction through a calmodulin-dependent pathway.
Acetylcholine ; Arachidonic Acid ; Cyclic ADP-Ribose ; Cytosol ; Esophageal Sphincter, Lower ; GTP-Binding Proteins ; Hydrolysis ; Inositol ; Intestines ; Metabolism ; Molecular Weight ; Muscle, Smooth* ; Myocytes, Smooth Muscle ; Myosin Light Chains ; Myosin-Light-Chain Kinase ; Negotiating ; Phosphatidylcholines ; Phosphatidylinositols ; Phospholipase D ; Phospholipases ; Phospholipases A2 ; Phosphorylation ; Phosphotransferases ; Protein Kinase C ; Receptor, Muscarinic M3 ; Receptors, Muscarinic ; Second Messenger Systems ; Type C Phospholipases ; Whooping Cough