To examine the expression of phospholipase A2 receptor (PLA2R) in renal tissues and the level of anti-PLA2R antibody in serum in patients with idiopathic membranous nephropathy (IMN) and secondary membranous nephropathy (SMN), and to evaluate their diagnostic value in IMN. Methods: A total of 73 patients, who were diagnosed between May, 2014 and February, 2015 in the Department of Nephrology of the Second Xiangya Hospital, Central South University, were divided into three groups: an IMN group (n=48), an SMN group (n=17) and a minimal change disease group (n=8) according to the renal biopsy. PLA2R expression in renal tissues and the level of anti-PLA2R antibody in serum were detected by indirect immunofluorescence technique. Results: The positive rate and fluorescence intensity for PLA2R in the renal tissues in the IMN group were higher than those in the SMN group (91.7% in the IMN group vs 29.4% in the SMN group, P<0.05), while the positive rate and serum level for anti-PLA2R antibody in the IMN group were higher than those in the SMN group (85.4% in the IMN group vs 29.4% in the SMN group, P<0.05); the expression of PLA2R in renal tissues and the serum level for anti-PLA2R antibody were not detected in the minimal change disease group. The serum level of anti-PLA2R antibody was positively correlated with 24 h urine protein (r=0.432, P<0.01) and negatively correlated with serum albumin (r=-0.307, P<0.05). Conclusion: The expression of PLA2R in renal tissues and the serum level of anti-PLA2R antibody might be potential markers for diagnosis of IMN.目的：检测特发性膜性肾病(idiopathic membranous nephropathy，IMN)、继发性膜性肾病(secondary membranous nephropathy，SMN)患者肾组织中磷脂酶A2受体(phospholipase A2 receptor，PLA2R)的表达及血清抗PLA2R抗体滴度，分析其在诊断IMN中的价值。方法：2014年5月至2015年2月中南大学湘雅二医院肾内科肾活检患者73例，分为IMN组(n=48)、SMN组(n=17)和微小病变性肾病组(n=8)。采用间接免疫荧光法检测各组肾组织PLA2R及血清抗PLA2R抗体的表达。结果：IMN组肾组织PLA2R阳性率为91.7%，SMN组阳性率为29.4%，IMN组阳性率、荧光强度明显高于SMN组(均P<0.05)；IMN组血清PLA2R抗体阳性率为85.4%，SMN组阳性率为29.4%，IMN组抗体阳性率及滴度明显高于SMN组(均P<0.05)；微小病变性肾病组肾组织PLA2R抗原及血清抗体均呈阴性。IMN组血清PLA2R抗体滴度与24 h尿蛋白呈正相关(r=0.432，P<0.01)，与血清白蛋白呈负相关(r=–0.307，P<0.05)。结论：检测肾组织PLA2R和血清PLA2R抗体的表达有助于IMN的诊断及鉴别诊断，监测血清PLA2R抗体滴度有助于评估疾病活跃程度和治疗效果。.
Background The efficacy of tonsillectomy in immunoglobulin A nephropathy (IgAN) remains controversial. The aim of the study was to conduct a randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgAN. Methods We randomly selected 98 patients with biopsy-proven IgA nephropathy and randomly allocated to receive tonsillectomy combined with drug therapy (Group A) or drug therapy alone (Group B). The participating patients were entered into a 4-year single-center study. Remission and relapse rate were calculated for hematuria and proteinuria using the Kaplan–Meier method. Results No differences were found between the two groups in their baseline clinical and histological characteristics. Patients with tonsillectomy exhibited considerable improvement in the following aspects compared to those patients who did not undergo tonsillectomy: time to reach first remission (3.1 vs. 24.9 months, p < 0.001) for hematuria and (2.5 vs. 26.1 months, p < 0.001) for proteinuria, cumulative remission rate (91.8% vs. 46.9%, p < 0.001 by log-rank test) for hematuria and (95.9% vs. 51.0%, p < 0.001) for proteinuria, the duration of first remission (26.5 vs. 11.8 months, p = 0.0047) for hematuria and (23.5 vs. 10.5 months, p = 0.0012) for proteinuria, as well as lower relapse rate for hematuria and proteinuria in Group A. Conclusion Our clinical data demonstrated that tonsillectomy could be beneficial for IgAN patients, particularly by contributing to faster and longer remission, as well as reducing the frequency of possible future relapses.
Abstract Background: Mitochondrial quality control (MQC) plays a critical role in the progression of tubulointerstitial injury in diabetic kidney disease (DKD). Mitochondrial unfolded protein response (UPRmt), an important MQC procedure, is activated to maintain mitochondrial protein homeostasis upon mitochondrial stress. Activating transcription factor 5 (ATF5) has been proved to be the key in mammalian UPRmt via its mitochondria-nuclear translocation. In this study, we investigated whether ATF5 activate UPRmt in mammalian DKD to reduce tubule injury. Methods: Eight-week-old db/db mice were injected with ATF5-shRNA lentivirus or negative control lentivirus via the tail vein. Mice were euthanized at 12 weeks, DHE and Tunel assay were performed respectively to evaluate the apoptosis and ROS production of kidney section. And we used western blotting to detect the expression relationship between ATF5 and UPRmt. ATF5-siRNA, ATF5 overexpression plasmid or HSP60-siRNA were transfected into HK-2 cells. Mitosox and DCFH-DA staining methods were used to gauging cell and mitochondial oxidative stress level, while early stage of cell apoptosis was detected by JC-1 kit. Results: We found that UPRmt intensified and exhibited opposite function in HK-2 cells in respond to high glucose intervention. We showed that compared with non-diabetic samples, renal section from patients and mice with diabetes showed increase expression of ATF5 and UPRmt related proteins (HSP60, CLpP, LONP1), which were correlated with tubule damage of kidney. We also established 12-week-old ATF5 knocking-down db/db mice, and found they presented improved biochemical and histological features and lower expression of UPRmt related proteins as compared with db/db mice. Correspondingly, HG-induced oxidative stress damage, apoptosis and UPRmt were reversed by ATF5-siRNA in HK-2 cells and aggravated by ATF5 over-expressing plasmid. Moreover, overexpressing ATF5 and down-regulating HSP60 simultaneously offset the effect of ATF5 overexpressing plasmid. Conclusions: Our findings suggest that ATF5 is closely associated with the progress of damage in diabetic kidney tubule cells by regulating UPRmt.
To evaluate the value of thrombospond in Type I domain-containing 7A (THSD7A) and M-type phospholipase A2 receptor (PLA2R) in primary membranous nephropathy (PMN) and to explore the relationship between their antibody levels and prognosis.Renal tissues in 128 patients with membranous nephropathy in the Second Xiangya Hospital of Central South University were collected from February 2015 to August 2017, including 108 patients with primary membranous nephropathy (PMN group) and 20 patients with secondary membranous nephropathy (SMN) (SMN group). Indirect immunofluorescence method was used to detect the expression of PLA2R antigen in kidney tissues,and the glomerular expression of THSD7A antigen was examined by immunohistochemistry and indirect immunofluorescence. The serum levels of anti-PLA2R antibodies and THSD7A antibodies were also detected by ELISA. According to the results of PMN examination,the patients were also divided into a PLA2R-related membranous nephropathy group and a THSD7A-related membranous nephropathy group.The positive rate of PLA2R in the renal tissues in the PMN group was higher than that in the SMN group (78% in the PMN group, 35% in the SMN group, P<0.01),while the positive rate of anti-PLA2R antibody in the PMN group was also higher than that in the SMN group (50% in the PMN group, 25% in the SMN group, P<0.05).The serum level of anti-PLA2R antibody was positively correlated with 24 h urine protein (r=0.254, P<0.05) and negatively correlated with serum albumin (r=-0.236, P<0.05). The expression of THSD7A was positive in glomeruli in 7 cases of the PMN group (6%) by immuno-histochemistry, and which was positive in 1case of the SMN group (5%).The serum levels of anti-THSD7A antibody in the PMN group were higher than those in the SMN group [(0.49±0.26) pg/mL in the PMN group,(0.34±0.27) pg/mL in the SMN group, P<0.05]. There was no difference in the clinical characteristics between the PLA2R-related membranous nephropathy group and the THSD7A-related membranous nephropathy group.PLA2R and THSD7A are the target antigen of PMN, and the associated autoantibodies are helpful for the differential diagnosis of PMN. The anti-PLA2R antibody levels can reflect the severity of the disease and evaluate the effect of treatment. The incidence of THSD7A membranous nephropathy is low, and monitoring the serum anti-THSD7A antibody levels can assess patients' condition and predict disease outcome.目的: 探讨M型磷脂酶A2受体(phospholipase A2 receptor，PLA2R)、1型血小板反应蛋白7A域(thrombospondin Type 1 domain-containing 7A，THSD7A)及相应的抗体对特发性膜性肾病(primary membranous nephropathy，PMN)的诊断价值及其血清抗体水平与预后的关系。方法: 纳入2015年2月至2017年8月中南大学湘雅二医院肾内科行肾活检确诊的膜性肾病128例，其中PMN108例(PMN组)，继发性膜性肾病(secondary membranous nephropathy，SMN)20例(SMN组)。应用间接免疫荧光法检测肾组织PLA2R抗原表达，间接免疫荧光法和免疫组织化学法检测肾组织THSD7A抗原表达，ELISA检测血清PLA2R和THSD7A的抗体水平。根据检测结果，又将患者分为PLA2R相关性膜性肾病组和THSD7A相关性膜性肾病组。结果: PMN组肾小球PLA2R阳性率明显高于SMN组(分别为72%和35%，P<0.01)，PMN组血清PLA2R抗体阳性率亦明显高于SMN组(分别为50%和25%，P<0.05)。PMN组血清PLA2R抗体与24 h尿蛋白量呈正相关关系(r=0.254，P<0.05)，与血清白蛋白呈负相关关系(r=-0.236，P<0.05)。PMN组中7例(6%)患者肾小球THSD7A呈阳性，SMN组有1例(5%)患者肾小球THSD7A呈阳性。PMN组血清THSD7A抗体水平明显高于SMN组[分别为(0.49±0.26)和(0.34±0.27) pg/mL，P<0.05]。7例THSD7A相关性膜性肾病组与86例PLA2R相关性膜性肾病组的临床病理特征差异均无明显统计学意义(均P>0.05)。结论: 肾组织PLA2R和THSD7A是PMN的靶抗原，其血清抗体有助于PMN的鉴别诊断；PLA2R抗体水平可反映病情严重程度，可用来评估治疗效果；PMN患者THSD7A相关性膜性肾病的发病率低，监测血清THSD7A抗体水平可评估患者病情，并可预测疾病转归。.
To explore tubulointerstitial nephritis antigen (TIN-ag) expression of chronic kidney disease (CKD) patients' renal tissue and the correlation to clinical phenotype.Through digital drawing lots, a total of 77 CKD patients from October 2012 to February 2013 at our department were randomly selected. All of them underwent biopsy. Based upon their pathological findings, they were divided into 2 groups of minimal change disease (MCD) and non-minimal change disease (NMCD). The stains of hematoxylin and eosin and Masson were used to observe renal pathological changes and immunofluorescence for detecting the TIN-ag expression of kidney tissue. The serum levels of creatinine, blood urea nitrogen, estimated glomerular filtration rate (eGFR), 24-hour urine output, 24-hour urine protein, α1-microglobulin, β2-microglobulin, pathological casts, N-acetyl-beta-glucosaminidase (NAG), specific gravity and other clinical parameters were monitored to examine their relationship between renal tissue TIN-ag expression.TIN-ag expression was distinct in renal tubular basement membrane of MCD patients while weak in primary focal segmental glomerulosclerosis (FSGS)(n = 16), IgA nephropathy (n = 23), MN (n = 14) and LN (n = 15) renal tissue. Immunofluorescence quantitative analysis showed that tubular TIN-ag fluorescence intensity of NMCD group was significantly lower than that of MCD group (4.84(3.02, 10.73) vs 20.79(8.19, 37.00), P < 0.01). In addition, TIN-ag expression in renal interstitial collagen area deposition of 0 grade group was higher than that of collagen area deposition 1-3 grades group (all P < 0.05). Serum α1-microglobulin and pathological urine cast, 24-hour urine protein of CKD patients were negatively correlated with kidney tubules TIN-ag expression (r = -0.312, -0.298, -0.214, all P < 0.05). Serum creatinine, blood urea nitrogen, serum β2-microglobulin and eGFR of CKD patients had no significant correlations with TIN-ag expression (P > 0.05). TIN-ag expression of CKD patients with lower expression levels of NAG was significantly higher than that of normal levels of NAG expression. TIN-ag expression of low urine specific gravity group was lower than that of normal urine specific gravity group (P < 0.05).TIN-ag expression of renal tissue tubule basement membrane in NMCD group is significantly lower than that in MCD group. TIN-ag expression is negatively correlated with renal tissue fibrosis. Expression of serum α1-microglobulin and concentrations of urinary pathology tube, 24-hour urine protein, NAG expression and urine specific gravity are negatively correlated with renal tissue TIN-ag expression in CKD patients.
Rationale: Cisplatin, a potent chemotherapeutic drug, induces side effects in normal tissues including the kidney.To reduce the side effects, repeated low-dose cisplatin (RLDC) is commonly used in clinical setting.While RLDC reduces acute nephrotoxicity to certain extents, a significant portion of patients later develop chronic kidney problems, underscoring the need for novel therapeutics to alleviate the long-term sequelae of RLDC therapy.Methods: In vivo, the role of HMGB1 was examined by testing HMGB1 neutralizing antibodies in RLDC mice.In vitro, the effects of HMGB1 knockdown on RLDC-induced nuclear factor-κB (NF-κB) activation and fibrotic phenotype changes were tested in proximal tubular cells.To study signal transducer and activator of transcription 1 (STAT1), siRNA knockdown and its pharmacological inhibitor Fludarabine were used.We also searched the Gene Expression Omnibus (GEO) database for transcriptional expression profiles and evaluated kidney biopsy samples from CKD patients to verify the STAT1/HMGB1/NF-κB signaling axis.Results: We found that RLDC induced kidney tubule damage, interstitial inflammation, and fibrosis in mice, accompanied by up-regulation of HMGB1.Blockage of HMGB1with neutralizing antibodies and Glycyrrhizin suppressed NF-κB activation and associated production of pro-inflammatory cytokines, reduced tubular injury and renal fibrosis, and improved renal function after RLDC treatment.Consistently, knockdown of HMGB1 decreased NF-κB activation and prevented the fibrotic phenotype in RLDC-treated renal tubular cells.At the upstream, knockdown of STAT1 suppressed HMGB1 transcription and cytoplasmic accumulation in renal tubular cells, suggesting a critical role of STAT1 in HMGB1 activation.Upregulation of STAT1/HMGB1/NF-κB along with inflammatory cytokines was also verified in kidney tissues of CKD patients.Conclusion: These results unravel the STAT1/HMGB1/NF-κB pathway that contributes to persistent inflammation and chronic kidney problems after cisplatin nephrotoxicity, suggesting new therapeutic targets for kidney protection in cancer patients receiving cisplatin chemotherapy.
IgA nephropathy (IgAN) has been considered to be the most frequent form of primary glomerulonephritis that occurs worldwide with a variety of factors involved in its occurrence and development. The impact of autophagy in IgAN, however, remains partially unclear. This study was designed to investigate the effects of rapamycin in an IgAN model.After establishing an IgAN rat model, SD rats were divided into 4 groups: control, control + rapamycin, IgAN, IgAN + rapamycin. Proteinuria and the pathological changes and the level of autophagy of kidney were texted. Identify the expression of phosphorylation and total mammalian target of rapamycin (mTOR) and s6k1 as well as cyclin D1 in the kidney of rats through Western blot and immunohistochemistry.With rapamycin treatment, we observed a significant reduction in the progression of proteinuria as well as alleviation of pathological lesions in IgAN rats. Besides, autophagy was inhibited, while the mTOR/S6k1 pathway was activated and expression of cyclin D1 was increased in IgAN. Rapamycin treatment increased autophagy and decreased the expression of cyclin D1.These results may suggest that mTOR-mediated autophagy inhibition may result in mesangial cell proliferation in IgAN.
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