ADAM10 mediates ectopic proximal tubule development and renal fibrosis through Notch signalling

Disturbed intrauterine development increases the risk of renal disease. Various studies have reported that Notch signalling plays a significant role in kidney development and kidney diseases. A disintegrin and metalloproteinase domain 10 (ADAM10), an upstream protease of the Notch pathway, is also reportedly involved in renal fibrosis. However, how ADAM10 interacts with the Notch pathway and causes renal fibrosis is not fully understood. In this study, using a prenatal chlorpyrifos (CPF) exposure mouse model, we investigated the role of the ADAM10/Notch axis in kidney development and fibrosis. We found that prenatal CPF-exposure mice presented overexpression of Adam10, Notch1 and Notch2, and led to premature depletion of Six2⁺ nephron progenitors and ectopic formation of proximal tubules (PTs) in the embryonic kidney. These abnormal phenotypic changes persisted in mature kidneys due to the continuous activation of ADAM10/Notch and showed aggravated renal fibrosis in adults. Finally, both ADAM10 and NOTCH2 expression were positively correlated with the degree of renal interstitial fibrosis in IgA nephropathy patients, and increased ADAM10 expression was negatively correlated with decreased kidney function evaluated by serum creatinine, cystatin C, and estimated glomerular filtration rate. Regression analysis also indicated that ADAM10 expression was an independent risk factor for fibrosis in IgAN. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.     

Decreased serum thrombospondin-1 and elevation of its autoantibody are associated with multiple exacerbated clinical manifestations in systemic lupus erythematosus

The pathological effects of thrombospondin-1 (TSP-1) have been studied in many preclinical tumor models and rheumatoid arthritis. However, the role of TSP-1 and anti-thrombospondin-1 autoantibodies (ATSA) in systemic lupus erythematosus (SLE) has not been specifically defined. In this study, we investigated the clinical relevance and functional significance of TSP-1 and ATSA in SLE patients. Serum levels of TSP-1 and ATSA were measured by ELISA in 138 adult SLE patients and 60 healthy controls. Blood cell counts, rheumatoid factor (RF), immunoglobulins, erythrocyte sedimentation rate (ESR), complements, and SLE-related autoantibodies were measured by standard laboratory techniques. Disease activity was assessed by systemic lupus erythematosus disease activity index (SLEDAI). TSP-1 concentrations were significantly lower in SLE patients compared with those in healthy controls. A significant difference of TSP-1 was observed in the patients with serositis, C3 decrease, RF positive, leukocytopenia, and thrombocytopenia. The levels of TSP-1 showed a positive correlation with the number of leukocyte and thrombocyte, while a negative correlation with anti-dsDNA antibody, IgG, ESR, and SLEDAI. ATSA was observed in 58.7% (81/138) of SLE patients, which was significantly higher than that in healthy controls (7/60, p?<?0.05). Patients with active SLE showed higher ATSA positivity (67.1%) than those with inactive disease (47.1%, p?<?0.05). ATSA was positively correlated with anti-rRNP antibody, IgG, total protein, and C4. This study revealed the opposite clinical relevance of TSP-1 and its autoantibody in SLE for the first time. TSP-1 may play an anti-inflammatory and immunoregulatory role in SLE autoimmunity. ATSA increased more frequently in disease-active patients and was associated with more severe clinical manifestations, which implicated its antagonistic role on TSP-1 and its involvement in the pathogenesis of SLE.     

Diagnostic performance of pulmonary ultrasonography and a clinical score for the evaluation of fluid overload in haemodialysis patients

IntroductionThere is no feasible benchmark in daily routine to estimate the hydration status of haemodialysis patients, which is essential to their management.ObjectiveWe performed a study in haemodialysis patients to assess the diagnostic performance of pulmonary ultrasound and clinical examination for the evaluation of fluid overload using transthoracic echocardiography as a gold standard.MethodsThirty-one patients receiving chronic haemodialysis patients were included. Evaluation of hydration status was assessed weekly before haemodialysis sessions using clinical and Echo Comet Score from pulmonary ultrasound and transthoracic echocardiography (reference method).ResultsFive patients had a transthoracic echocardiography overload. Compared with transthoracic echocardiography, the diagnostic performance of the clinical overload score has a sensitivity of 100%, a specificity of 77%, a positive predictive value of 50% and a negative predictive value of 100% with a κ of 0.79. Only orthopnoea (P = 0.008), jugular turgor (P = 0.005) and hepatic-jugular reflux (P = 0.008) were significantly associated with transthoracic echocardiography overload diagnosis. The diagnostic performance of Echo Comet Score by pulmonary ultrasound has a sensitivity of 80%, a specificity of 58%, a positive predictive value of 26% and a negative predictive value of 94%. Ten patients (32.3%) had an increase of extravascular pulmonary water without evidence of transthoracic echocardiography or clinical overload.ConclusionsOur clinical score has a convincing diagnostic performance compared to transthoracic echocardiography and could be easily used in daily clinical routine to adjust dry weight. The evaluation of the overload using pulmonary ultrasound seems poorly correlated with the overload evaluated by transthoracic echocardiography. Extravascular pulmonary water undetected by clinical examination and transthoracic echocardiography remains a parameter that requires further investigation.     

MiR-143-3p controls TGF-β1-induced cell proliferation and extracellular matrix production in airway smooth muscle via negative regulation of the nuclear factor of activated T cells 1

MicroRNAs (miRNAs) are small noncoding RNAs that function in diverse biological processes. However, little is known about the precise role of microRNAs in the functioning of airway smooth muscle cells (ASMCs). Here, we investigated the potential role and mechanisms of the miR-143 -3p on proliferation and the extracellular matrix (ECM) protein production of ASMCs. We demonstrated that miR-143-3p was aberrantly lower in ASMCs isolated from individuals with asthma than in individuals without asthma. Meanwhile, TGF-β1 caused a marked decrease in a time-dependent manner in miR-143-3p expression in ASMCs from asthmatics. Additionally, the overexpression of miR- 143-3p robustly reduced TGF-β1-induced ASMCs proliferation and downregulated CDK and cyclin expression, whereas the inhibition of miR-143-3p significantly enhanced ASMCs proliferation and upregulated the level of CDKs and cyclins. Re-expression of miR-143-3p attenuated ECM protein deposition reflected as a marked decrease in the expression of type I collagen and fibronectin, whereas miR-143-3p downregulation caused an opposite effect on the expression of type I collagen and fibronectin. Moreover, qRT-PCR and western blot analysis indicated that miR-143-3p negatively regulated the expression of nuclear factor of activated T cells 1 (NFATc1). Subsequent analyses demonstrated that NFATc1 was a direct and functional target of miR-143-3p, which was validated by the dual luciferase reporter assay. Most importantly, the overexpression of NFATc1 effectively reversed the inhibition of miR-143-3p on TGF-β1-induced proliferation, and strikingly abrogated the effect of miR-143-3p on the expression of CDK4 and Cyclin D1. Together, miR-143-3p may function as an inhibitor of asthma airway remodeling by suppressing proliferation and ECM protein deposition in TGF-β1-mediated ASMCs via the negative regulation of NFATc1 signaling, suggesting miR-143-3p as a potential therapeutic target for asthma.     

Therapeutic effect of leflunomide on the development of experimental lupus nephritis in mice

Mice with chronic graft-versus-host disease (cGVHD) induced by transferring parental BALB/C lymphocytes into (C57BL/6 × BALB/C) F1 (CBF1) hybrids, develop a syndrome characterized by B-cell hyperactivity, autoantibody production, and immune complex-mediated glomerulonephritis. In this model, we evaluated the role of leflunomide on the development of lupus nephritis in system autoimmunity. Daily administration of leflunomide (15 mg/kg/d) from 2 weeks after cGVHD induction can dramatically reduce the production of autoantibodies and immune complex deposition in the kidney, leading to relieved kidney damage and reduced mortality. The therapeutic effect of leflunomide on the lupus-prone mice was partially due to the inhibition of TLR9 signaling pathway, which was an important component of innate immune system.     

雷公藤多苷联合厄贝沙坦对IgA肾病疗效及尿足细胞排泄的影响

背景　IgA肾病是全球最常见的原发性肾小球疾病,也是导致终末期肾功能衰竭（ESRD）的常见原因。目前临床上主要采用雷公藤多苷、厄贝沙坦等免疫抑制剂进行治疗,但两者是否具有协同作用从根源上缓解IgA肾病的进展尚未被证实。目的　探讨雷公藤多苷联合厄贝沙坦治疗IgA肾病患者的疗效及其对尿足细胞排泄的影响。方法　根据纳入与排除标准,选取2014年1月-2016年12月河南省人民医院收治的IgA肾病患者128例为研究对象。根据治疗方式,将研究对象分为雷公藤多苷组（42例）、厄贝沙坦组（40例）和联合治疗组（46例）。雷公藤多苷组口服雷公藤多苷片20 mg/次,3次/d;厄贝沙坦组口服厄贝沙坦片150 mg/次,2次/d;联合治疗组同时服用雷公藤多苷片（20 mg/次,3次/d）和厄贝沙坦片（150 mg/次,2次/d）;所有患者治疗12周。收集患者一般资料,治疗前后血压（收缩压、舒张压）、实验室指标〔血肌酐（Scr）、血尿素氮（BUN）、血尿酸（SUA）、血清清蛋白（Alb）、总胆固醇（TC）、估算肾小球滤过率（eGFR）、24 h尿蛋白〕,尿蛋白缓解效果及不良反应,治疗前后尿足细胞。结果　联合治疗组治疗后Alb高于雷公藤多苷组、厄贝沙坦组,治疗后24 h尿蛋白低于雷公藤多苷组、厄贝沙坦组（P<0.05）。雷公藤多苷组、厄贝沙坦组、联合治疗组治疗后Scr、24 h尿蛋白均低于本组治疗前,治疗后Alb、eGFR均高于本组治疗前（P<0.05）;联合治疗组治疗后BUN、SUA低于本组治疗前（P<0.05）。联合治疗组治疗有效率高于雷公藤多苷组、厄贝沙坦组（P<0.05）。3组不良反应发生率比较,差异无统计学意义（P>0.05）。联合治疗组治疗后尿足细胞少于雷公藤多苷组、厄贝沙坦组（P<0.05）。雷公藤多苷组、厄贝沙坦组、联合治疗组治疗后尿足细胞均少于本组治疗前（P<0.05）。结论　雷公藤多苷联合厄贝沙坦治疗IgA肾病患者疗效及减少尿足细胞排泄的效果优于单一雷公藤多苷或厄贝沙坦治疗方案,即二药联用对肾足细胞损伤具有更好的协同保护作用,从而延缓了病情的进展。     

Magnetic resonance imaging of cartilaginous tumors: a retrospective study of 79 patients

Objective: Hyaline cartilaginous tumors are characterized by extremely high signal intensity on T2-weighted images. Recently, some distinctive MR features of cartilaginous bone tumors were reported in small series. Low signal intensity septa surrounding high signal intensity cartilage lobules were seen on T2-weighted images in low-grade chondrosarcomas. On spin-echo T1-weighted images after Gd contrast injection, marked ‘septal’ or ‘ring-and-arc’ enhancement was observed in low-grade chondrosarcomas and enchondromas. The purpose of this study was to determine sensitivity and specificity of these MR findings in diagnosis of cartilaginous tumors, and to assess the value of MR in diagnostic workup of these lesions. Materials and methods: Retrospective evaluation of MR findings in 79 cartilaginous tumors and in 79 non-cartilaginous tumors. All lesions were biopsy proven. Each MR examination was independently reviewed by two experienced radiologists without knowledge of clinical data, radiographic and/or CT findings, or histological diagnosis. All lesions were evaluated for morphology (lobular or non-lobular), presence of a high signal intensity mass on T2-weighted images, presence of low signal intensity septa separating high signal intensity lobules on T2-weighted images, and evidence of septal (‘ring-and-arc’) enhancement.Results: None of the reviewed parameters is useful in diagnosing osteochondromas. Since osteochondromas have a characteristic appearance on plain radiography, the value of MR imaging in the workup of these lesions remains limited. MR findings in enchondromas have a low specificity and a low sensitivity. Low-grade chondrosarcomas, often hard to diagnose on plain radiography and difficult to differentiate from enchondromas, are characterized by the MR tandem of ‘low signal intensity septa on T2-weighted images’ together with ‘septal or ring-and-arc enhancement’ (sensitivity 92.3%, specificity 76.5%). High-grade chondrosarcomas are easily recognized on plain radiography. Conclusions: In differentiating cartilaginous from non-cartilaginous tumors, MR features are highly specific but lack sensitivity. Grading potentials of MR parameters are promising due to the high accuracy in diagnosing low-grade chondrosarcomas.     

Sputum containing zinc enhances carbapenem resistance,biofilm formation and virulence of Pseudomonas aeruginosa

Pseudomonas aeruginosa chronic lung infections are the leading cause of mortality in cystic fibrosis patients, a serious problem which is notably due to the numerous P. aeruginosa virulence factors, to its ability to form biofilms and to resist the effects of most antibiotics. Production of virulence factors and biofilm formation by P. aeruginosa is highly coordinated through complex regulatory systems. We recently found that CzcRS, the zinc and cadmium-specific two-component system is not only involved in metal resistance, but also in virulence and carbapenem antibiotic resistance in P. aeruginosa. Interestingly, zinc has been shown to be enriched in the lung secretions of cystic fibrosis patients. In this study, we investigated whether zinc might favor P. aeruginosa pathogenicity using an artificial sputum medium to mimic the cystic fibrosis lung environment. Our results show that zinc supplementation triggers a dual P. aeruginosa response: (i) it exacerbates pathogenicity by a CzcRS two-component system-dependent mechanism and (ii) it stimulates biofilm formation by a CzcRS-independent mechanism. Furthermore, P. aeruginosa cells embedded in these biofilms exhibited increased resistance to carbapenems. We identified a novel Zn-sensitive regulatory circuit controlling the expression of the OprD porin and modifying the carbapenem resistance profile. Altogether our data demonstrated that zinc levels in the sputum of cystic fibrosis patients might aggravate P. aeruginosa infection. Targeting zinc levels in sputum would be a valuable strategy to curb the increasing burden of P. aeruginosa infections in cystic fibrosis patients.