Expression of phospholipase A2 receptor in primary cultured podocytes derived from dog kidneys.
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SUBMITTER: Sugahara G
PROVIDER: S-EPMC4905851 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
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Expression of phospholipase A2 receptor in primary cultured podocytes derived from dog kidneys.
Sugahara Go G Kamiie Junichi J Kobayashi Ryosuke R Mineshige Takayuki T Shirota Kinji K
The Journal of veterinary medical science 20160206 5
Phospholipase A2 receptor (PLA2R) expressed in human podocytes has been highlighted as a causative autoantigen of human idiopathic membranous nephropathy. However, its expression was found to be minimal or absent in murine and rat podocytes. In this study, immunofluorescence revealed the expression of PLA2R in the glomerular podocytes in the kidney tissue sections of dogs. We then attempted to culture canine podocytes and investigate the expression of PLA2R in these cells. Glomeruli were isolate ...[more]
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Project description:IntroductionPrimary membranous nephropathy (PMN) is associated with the anti-phospholipase A2 receptor (anti-PLA2R) antibody in 70% of cases. Some anti-PLA2R-negative patients have the PLA2R antigen in renal tissue. This study examined the prognosis of patients with PMN according to their serum anti-PLA2R antibody (SAb) and glomerular PLA2R antigen (GAg) status.MethodsPatients diagnosed with PMN were included retrospectively. Patients were grouped according to their PLA2R status into the SAb-/GAg-, SAb-/GAg+, and SAb+/GAg + groups. Baseline data, renal biopsy results, treatment, and clinical data were compared among the groups. Cox univariable and multivariable analyses examined the factors related to complete remission (CR).ResultsA total of 114 patients were enrolled; 10 (9%) in the SAb-/GAg-, 23 (20%) in the SAb-/GAg+, and 81 (71%) in the SAb+/GAg+ groups. Cumulative CR rate showed a significant difference between the SAb-/GAg - and SAb+/GAg+ groups (log-rank p = 0.003). The multivariable Cox proportional hazard analysis showed that age (HR = 0.968; 95%CI = 0.946-0.990; p = 0.005), SAb+/GAg+ versus SAb-/GAg- (HR = 0.387; 95%CI = 0.190-0.788; p = 0.009), SAb-/GAg+ versus SAb-/GAg- (HR = 0.398; 95%CI = 0.169, 0.939; p = 0.035), total renal chronicity score ≥2 (HR = 0.461, 95%CI: 0.277-0.766, p = 0.003), and IgA deposition (HR = 2.596; 95%CI = 1.227-5.492; p = 0.013) were all independently related (p < 0.05) to CR.ConclusionsThe SAb and GAg status was an indicator of PMN prognosis. The patients with SAb-/GAg - had an increased likelihood of achieving CR than those with SAb-/GAg+ and SAb+/GAg+.
| S-EPMC7470143 | biostudies-literature
Project description:BackgroundIt has recently been proposed that the M-type phospholipase A2 receptor (PLA2R1) acts as a tumour suppressor in certain malignancies including mammary cancer. Considering that DNA methylation is an important regulator of gene transcription during carcinogenesis, in the current study we analyzed the PLA2R1 expression, PLA2R1 promoter methylation, and selected micro RNA (miRNA) levels in normal human mammary epithelial cells (HMEC) and cancer cell lines.MethodsLevels of PLA2R1 and DNA methyltransferases (DNMT) specific mRNA were determined using real-time RT-PCR. Methylation specific-high resolution melting (MS-HRM) analysis was utilized to quantify the methylation degree of selected CpG sites localized in the promoter region of the PLA2R1 gene. Expression of miRNA was tested using miScript Primer Assay system.ResultsNearly complete methylation of the analyzed PLA2R1 promoter region along with PLA2R1 gene silencing was identified in MDA-MB-453 mammary cancer cells. In MCF-7 and BT-474 mammary cancer cell lines, a higher DNA methylation degree and reduced PLA2R1 expression were found in comparison with those in normal HMEC. Synergistic effects of demethylating agent (5-aza-2'-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) on PLA2R1 transcription in MDA-MB-453 cells confirmed the importance of DNA methylation and histone modification in the regulation of the PLA2R1 gene expression in mammary cells. Furthermore, significant positive correlation between the expression of DNMT1 and PLA2R1 gene methylation and negative correlation between the cellular levels of hsa-mir-141, -181b, and -181d-1 and the expression of PLA2R1 were identified in the analyzed cells. Analysis of combined z-score of miR-23b, -154 and -302d demonstrated a strong and significant positive correlation with PLA2R1 expression.ConclusionsOur data indicate that (i) PLA2R1 expression in breast cancer cells is controlled by DNA methylation and histone modifications, (ii) hypermethylation of the PLA2R1 promoter region is associated with up-regulation of DNMT1, and (iii) hsa-miR-23b, -154, and -302d, as well as hsa-miR-141, -181b, and -181d-1 are potential candidates for post-transcriptional regulation of PLA2R1 expression in mammary cancer cells.
| S-EPMC4682251 | biostudies-literature
Project description:Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, with an uncertain clinical outcome. The characterization of the phospholipase A2 receptor (PLA2R) as the major target antigen in primary MN and the detection of circulating autoantibodies in these patients is a major advance in understanding this disease. To test whether PLA2R antibody levels reflect disease activity or clinical outcome, we performed a prospective multicenter study of 133 adult patients with primary MN and detectable serum PLA2R antibodies who had not received immunosuppressive therapy. Patients were followed ≤24 months. PLA2R antibody levels associated with clinical disease activity (proteinuria) in patients with immunosuppressive therapy (n=101) or supportive care (n=32). Within 3 months, immunosuppressive therapy led to a sustained 81% reduction in PLA2R antibody levels paralleled by a 39% reduction in proteinuria. Patients who experienced remission of proteinuria after 12 months had significantly lower PLA2R antibody levels at the time of study inclusion compared with patients with no remission. Patients with high PLA2R antibody levels achieved remission of proteinuria significantly later than patients with low PLA2R antibody levels. PLA2R antibody levels fell over time in patients with spontaneous remission but remained elevated in patients who did not show a reduction in proteinuria. Multivariable Cox regression analysis confirmed PLA2R antibody level as an independent risk factor for not achieving remission of proteinuria. We conclude that a decrease in PLA2R antibody level is associated with a decrease of proteinuria in patients with primary MN.
| S-EPMC4033365 | biostudies-literature
Project description:Growing evidence suggests that renal purinergic signaling undergoes significant remodeling during pathophysiological conditions such as diabetes. This study examined the renal P2 receptor profile and ATP-mediated calcium response from podocytes in glomeruli from kidneys with type 1 or type 2 diabetic kidney disease (DKD), using type 2 diabetic nephropathy (T2DN) rats and streptozotocin-injected Dahl salt-sensitive (type 1 diabetes) rats. A dramatic increase in the ATP-mediated intracellular calcium flux in podocytes was observed in both models. Pharmacological inhibition established that P2X4 and P2X7 are the major receptors contributing to the augmented ATP-mediated intracellular calcium signaling in diabetic podocytes. The transition in purinergic receptor composition from metabotropic to ionotropic may disrupt intracellular calcium homeostasis in podocytes resulting in their dysfunction and potentially further aggravating DKD progression.
| S-EPMC8188476 | biostudies-literature
Project description:Background and objectivesLoss of renal function in patients with primary membranous nephropathy cannot be reliably predicted by laboratory or clinical markers at the time of diagnosis. M-type phospholipase A2 receptor autoantibodies have been shown to be associated with changes in proteinuria. Their eventual effect on renal function, however, is unclear.Design, setting, participants, & measurementsIn this prospective, open, multicenter study, the potential role of M-type phospholipase A2 receptor autoantibodies levels on the increase of serum creatinine in 118 consecutive patients with membranous nephropathy and positivity for serum M-type phospholipase A2 receptor autoantibodies was analyzed. Patients were included in the study between April of 2010 and December of 2012 and observed until December of 2013. The clinical end point was defined as an increase of serum creatinine by ≥ 25% and serum creatinine reaching ≥ 1.3 mg/dl.ResultsPatients were divided into tertiles according to their M-type phospholipase A2 receptor autoantibody levels at the time of inclusion in the study: tertile 1 levels=20-86 units/ml (low), tertile 2 levels=87-201 units/ml (medium), and tertile 3 levels ≥ 202 units/ml (high). The median follow-up time of all patients in the study was 27 months (interquartile range=18-33 months). The clinical end point was reached in 69% of patients with high M-type phospholipase A2 receptor autoantibodies levels (tertile 3) but only 25% of patients with low M-type phospholipase A2 receptor autoantibodies levels. The average time to reach the study end point was 17.7 months in patients with high M-type phospholipase A2 receptor autoantibodies levels and 30.9 months in patients with low M-type phospholipase A2 receptor autoantibodies levels. A multivariate Cox regression analysis showed that high M-type phospholipase A2 receptor autoantibodies levels-in addition to men and older age-are an independent predictor for progressive loss of renal function.ConclusionsHigh M-type phospholipase A2 receptor autoantibodies levels were associated with more rapid loss of renal function in this cohort of patients with primary membranous nephropathy and therefore, could be helpful for treatment decisions.
| S-EPMC4220763 | biostudies-literature
Project description:BACKGROUND:Immunosuppressant drugs reduce proteinuria and anti-phospholipase A2 receptor autoantibodies (PLA2R-Ab) in primary membranous nephropathy (PMN) with varying success and associated toxicities. This study aimed to evaluate the effect of belimumab on proteinuria and PLA2R-Ab in participants with PMN. METHODS:In this prospective, open-label, experimental medicine study, 14 participants with PMN and persistent nephrotic-range proteinuria received up to 2 years belimumab monotherapy (10 mg/kg, every 4 weeks). Changes in proteinuria (urinary protein:creatinine ratio), PLA2R-Ab, albumin, cholesterol, B-cell subsets and pharmacokinetics were analysed during treatment and up to 6 months after treatment. RESULTS:Eleven participants completed to the primary endpoint (Week 28) and nine participants completed the study. In the intention-to-treat population population, baseline proteinuria of 724 mg/mmol [95% confidence interval (CI) 579-906] decreased to 498 mg/mmol (95% CI 383-649) and 130 mg/mmol (95% CI 54-312) at Weeks 28 and 104, respectively, with changes statistically significant from Week 36 (n = 11, P = 0.047). PLA2R-Ab decreased from 174 RU/mL (95% CI 79-384) at baseline to 46 RU/mL (95% CI 16-132) and 4 RU/mL (95% CI 2-6) at Weeks 28 and 104, respectively, becoming statistically significant by Week 12 (n = 13, P = 0.02). Nine participants achieved partial (n = 8) or complete (n = 1) remission. Participants with abnormal albumin and/or cholesterol at baseline gained normal/near normal levels by the last follow-up. Adverse events were consistent with those expected in this population. CONCLUSIONS:Belimumab treatment in participants with PMN can reduce PLA2R-Ab and subsequently proteinuria, important preludes to remission induction.
| S-EPMC7139214 | biostudies-literature
Project description:BackgroundThe anti-phospholipase A2 receptor (PLA2R) antibody is a non-invasive diagnostic tool and prognosis predictor of idiopathic membranous nephropathy (IMN). Baseline hypercholesterolemia independently predicts proteinuria outcomes in IMN patients. Thus, we investigated whether hyperlipidemia is correlated with anti-PLA2R and pathological indicators.MethodsA total of 495 IMN patients identified by kidney biopsy in Wuhan Tongji Hospital, China, from January 2016 through December 2020 were enrolled in this study. Data on clinical features, pathology findings, and outcomes were collected.ResultsTotal cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were positively related to proteinuria, indicating damage to the renal glomerulus [Spearman's rank correlation coefficient = 0.432, 0.462, 0.315, and 0.289, respectively, P < 0.001 for all]. In univariate logistic regression, low HDL-C [odds ratio (OR): 0.856; 95% CI: 0.778-0.939; P = 0.001] and high TG [OR: 1.025; 95% CI: 1.006-1.044; P = 0.011] were correlated with tubular atrophy, suggesting lesions on tubules. Increased TC [adjusted OR: 1.285; 95% CI: 1.119-1.475; P < 0.001], non-HDL-C [adjusted OR: 1.284; 95% CI: 1.113-1.482; P = 0.001], and LDL-C [adjusted OR: 1.178; 95% CI: 1.009-1.376; P = 0.039] independently predicted glomerular PLA2R deposit; similar results were observed for lipids in predicting the seropositivity of anti-PLA2R antibodies. After treatment, increased HDL-C [adjusted hazard ratio (HR): 1.764; 95% CI: 1.241-2.507; P = 0.002] and decreased non-HDL-C [adjusted HR: 0.884; 95% CI: 0.795-0.983; P = 0.022] independently predicted proteinuria remission.ConclusionHypercholesterolemia is a potentially useful biomarker for disease severity, serum anti-PLA2R antibody, glomerular PLA2R deposit, and proteinuria outcome of IMN.
| S-EPMC9248763 | biostudies-literature
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging that recapitulates many normal aging characteristics. This disorder is caused by mutation in the LMNA gene leading to the production of progerin which induces misshapen nuclei, cellular senescence, and aging. We previously showed that the phospholipase A2 receptor (PLA2R1) promotes senescence induced by replicative, oxidative, and oncogenic stress but its role during progerin-induced senescence and in progeria is currently unknown. Here, we show that knockdown of PLA2R1 prevented senescence induced by progerin expression in human fibroblasts and markedly delayed senescence of HGPS patient-derived fibroblasts. Whole-body knockout of Pla2r1 in a mouse model of progeria decreased some premature aging phenotypes, such as rib fracture and decreased bone content, together with decreased senescence marker. Progerin-expressing human fibroblasts exhibited a high frequency of misshapen nuclei and increased farnesyl diphosphate synthase (FDPS) expression compared to controls; knockdown of PLA2R1 reduced the frequency of misshapen nuclei and normalized FDPS expression. Pamidronate, a FDPS inhibitor, also reduced senescence and misshapen nuclei. Downstream of PLA2R1, we found that p53 mediated the progerin-induced increase in FDPS expression and in misshapen nuclei. These results suggest that PLA2R1 mediates key premature aging phenotypes through a p53/FDPS pathway and might be a new therapeutic target.
| S-EPMC6260922 | biostudies-literature
Project description:Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common. TNF superfamily members are key mediators of kidney injury. We have now identified key TNF receptor superfamily members in podocytes and explored the regulation of PLA2R expression and the impact of tacrolimus. Data mining of single cell transcriptomics and glomerular transcriptomics data identified TNFRSF12a/Fn14 as the highest expressed TNF receptor superfamily gene in human membranous nephropathy, and this was confirmed by immunohistochemistry that also identified NFκB activation in membranous nephropathy podocytes. Additionally, glomerular transcriptomics identified PLA2R1 expression as being increased in membranous nephropathy in the parenteral administration of the Fn14 ligand TWEAK increased podocyte PLA2R expression in mice. Furthermore, in cultured human podocytes, TWEAK increased the expression of PLA2R as well as the expression of other genes recently identified by GWAS as linked to membranous nephropathy: NFKB1 and IRF4. Interestingly, IRF4 encodes the FK506-binding protein 52 (FKBP52), a protein associated with tacrolimus. Tacrolimus prevented the increased expression of PLA2R, NFKB1 and IRF4 induced by TWEAK in cultured podocytes. In conclusion, TWEAK upregulates the expression of PLA2R and of other genes linked to membranous nephropathy in podocytes, and this is prevented by tacrolimus. An impact of tacrolimus on the expression of PLA2R and other genes in podocytes may underlie its efficacy in treating the disease as well as the frequent recurrence of nephrotic syndrome upon tacrolimus withdrawal.
| S-EPMC7408934 | biostudies-literature
Project description:The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing. Sixty patients had anti-PLA2R1 in serum or detectable PLA2R1 antigen in kidney tissue. We identified 18 sequence variants, comprising 2 not previously described, 7 reported as rare variants (<1%) in the Single Nucleotide Polymorphism Database or the 1000 Genomes project, and 9 known to be common polymorphisms. Although we confirmed significant associations among 6 of the identified common variants and iMN, only 9 patients had the private or rare variants, and only 4 of these patients were among the 60 who were PLA2R positive. In conclusion, rare variants in the coding sequence of PLA2R1, including splice sites, are unlikely to explain the pathogenesis of iMN.
| S-EPMC3609136 | biostudies-literature