BACKGROUND & AIMS: :Chronic hyperglycaemia in diabetes leads to the overproduction of free radicals and evidence is increasing that these contribute to the development of diabetic nephropathy. Among the spices, turmeric (Curcuma longa) is used as a flavouring and colouring agent in the indian diet every day and is known to possess anti-oxidant properties. The present study was designed to examine the effect of curcumin, a yellow pigment of turmeric, on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. Four weeks after STZ injection, rats were divided into four groups, namely control rats, diabetic rats and diabetic rats treated with curcumin (15 and 30 mg/kg, p.o.) for 2 weeks. Renal function was assessed by creatinine, blood urea nitrogen, creatinine and urea clearance and urine albumin excretion. Oxidative stress was measured by renal malonaldehyde, reduced glutathione and the anti-oxidant enzymes superoxide dismutase and catalase. Streptozotocin-injected rats showed significant increases in blood glucose, polyuria and a decrease in bodyweight compared with age-matched control rats. After 6 weeks, diabetic rats also exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance and proteinuria, along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key anti-oxidant enzymes. Chronic treatment with curcumin significantly attenuated both renal dysfunction and oxidative stress in diabetic rats. These results provide confirmatory evidence of oxidative stress in diabetic nephropathy and point towards the possible anti-oxidative mechanism being responsible for the nephroprotective action of curcumin.

背景与目标： ：糖尿病中的慢性高血糖症导致自由基的过度产生，并且越来越多的证据表明这些自由基有助于糖尿病性肾病的发展。在香料中，姜黄（姜黄）每天在印度饮食中用作调味剂和着色剂，并且已知具有抗氧化特性。本研究旨在检查姜黄素（一种姜黄黄色素）对链脲佐菌素（STZ）诱导的糖尿病大鼠肾功能和氧化应激的影响。在大鼠中通过腹膜内单次注射STZ（65 mg / kg）诱发糖尿病。注射STZ后四周，将大鼠分为四组，即对照大鼠，糖尿病大鼠和经姜黄素（15和30 mg / kg，口服）治疗2周的糖尿病大鼠。通过肌酐，血液尿素氮，肌酐和尿素清除率以及尿白蛋白排泄评估肾功能。通过肾脏丙二醛，还原型谷胱甘肽和抗氧化酶超氧化物歧化酶和过氧化氢酶来测定氧化应激。与年龄相称的对照大鼠相比，注射链脲佐菌素的大鼠显示血糖，多尿明显增加，体重下降。 6周后，糖尿病大鼠还表现出肾功能不全，这由肌酐和尿素清除率降低以及蛋白尿以及氧化应激显着增加所证实，氧化应激由脂质过氧化作用和关键抗氧化酶的活性决定。姜黄素的慢性治疗可显着减轻糖尿病大鼠的肾功能不全和氧化应激。这些结果提供了糖尿病性肾病中氧化应激的确证证据，并指出可能的抗氧化机制负责姜黄素的肾保护作用。

BACKGROUND & AIMS: :Pyodermatitis-pyostomatitis vegetans (PPV) constitutes an inflammatory mucocutaneous dermatosis that is associated with inflammatory bowel disease. Clinically, PPV appears as pustules on mucosal surfaces and as vegetating exudative plaques on intertriginous surfaces. It is typically a clinical diagnosis supported by histological findings. Microscopic findings include epidermal hyperplasia, focal acantholysis, and a dense mixed inflammatory infiltrate with intraepithelial and subepithelial eosinophilic microabscesses. In the recent literature, immunofluorescence has been thought to be negative in PPV or, if positive, an aberrant finding. Herein, we report 2 cases of PPV associated with inflammatory bowel disease, which display intercellular IgA deposits. Although these cases may represent isolated epiphenomena, it is possible that the paucity of PPV cases with immunofluorescent studies hitherto has led to an oversight of an interesting association between intercellular IgA and PPV.

背景与目标： ：脓皮炎-化脓性植物炎（PPV）构成了与炎症性肠病有关的炎症性粘膜皮肤性皮肤病。临床上，PPV在粘膜表面以脓疱的形式出现，在三叉间表面以植物性渗出性斑块出现。通常是组织学检查结果支持的临床诊断。显微镜下的发现包括表皮增生，局灶性棘层松解以及上皮内和上皮下嗜酸性微脓肿的致密混合炎性浸润。在最近的文献中，免疫荧光在PPV中被认为是阴性的，或者，如果阳性，则是异常的发现。在此，我们报告了2例与炎症性肠病相关的PPV病例，这些病例表现出细胞间IgA沉积物。尽管这些病例可能代表了孤立的现象，但迄今为止对PPV病例进行免疫荧光研究的可能性很低，导致对细胞间IgA与PPV之间有趣关系的疏忽。

BACKGROUND & AIMS: :Chronic exposure to high glucose leads to diabetic nephropathy characterized by increased mesangial matrix protein (e.g., collagen) accumulation. Altered cell signaling and gene expression accompanied by oxidative stress have been documented. The contribution of the tyrosine kinase, c-Src (Src), which is sensitive to oxidative stress, was examined. Cultured rat mesangial cells were exposed to high glucose (25 mmol/L) in the presence and absence of Src inhibitors (PP2, SU6656), Src small interfering RNA (siRNA), and the tumor necrosis factor-α-converting enzyme (TACE) inhibitor, TAPI-2. Src was investigated in vivo by administration of PP2 to streptozotocin (STZ)-induced diabetic DBA2/J mice. High glucose stimulated Src, TACE, epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2, p38), and collagen IV accumulation in mesangial cells. PP2 and SU6656 blocked high glucose-stimulated phosphorylation of Src Tyr-416, EGFR, and MAPKs. These inhibitors and Src knockdown by siRNA, as well as TAPI-2, also abrogated high glucose-induced phosphorylation of these targets and collagen IV accumulation. In STZ-diabetic mice, albuminuria, increased Src pTyr-416, TACE activation, ERK and EGFR phosphorylation, glomerular collagen accumulation, and podocyte loss were inhibited by PP2. These data indicate a role for Src in a high glucose-Src-TACE-heparin-binding epidermal growth factor-EGFR-MAPK-signaling pathway to collagen accumulation. Thus, Src may provide a novel therapeutic target for diabetic nephropathy.

背景与目标： ：长期暴露于高葡萄糖会导致糖尿病肾病，其特征是肾小球系膜基质蛋白（例如胶原蛋白）蓄积增加。已经记录了改变的细胞信号传导和基因表达并伴有氧化应激。检查了对氧化应激敏感的酪氨酸激酶c-Src（Src）的贡献。在存在和不存在Src抑制剂（PP2，SU6656），Src小干扰RNA（siRNA）和肿瘤坏死因子-α转化酶（TACE）的情况下，将培养的大鼠系膜细胞暴露于高葡萄糖（25 mmol / L）抑制剂，TAPI-2。通过对链脲佐菌素（STZ）诱导的糖尿病DBA2 / J小鼠施用PP2在体内研究了Src。高葡萄糖刺激的Src，TACE，表皮生长因子受体（EGFR），促分裂原激活的蛋白激酶（MAPK），细胞外信号调节激酶（ERK1 / 2，p38）和胶原IV在肾小球膜细胞中的蓄积。 PP2和SU6656阻止了Src Tyr-416，EGFR和MAPK的高葡萄糖刺激磷酸化。这些抑制剂和siRNA以及SAPI敲除的Src敲除也废除了这些靶标的高葡萄糖诱导的磷酸化和胶原IV的积累。在STZ糖尿病小鼠中，白蛋白尿，Src pTyr-416升高，TACE活化，ERK和EGFR磷酸化，肾小球胶原蛋白积聚和足细胞丢失均被PP2抑制。这些数据表明Src在高葡萄糖-Src-TACE-肝素结合表皮生长因子-EGFR-MAPK信号转导至胶原积累中的作用。因此，Src可以为糖尿病性肾病提供新的治疗靶标。

BACKGROUND & AIMS: :BK virus nephropathy (BKVN) is increasingly recognized as a major cause of renal allograft failure. Recent reports demonstrate that prompt reduction of immunosuppression upon detection of persistent viremia can be associated with resolution of viremia, with minimal risk of acute rejection (AR). However, these experiences in general have occurred in centers with low baseline risks of AR. It is possible that a finer balance between overimmunosuppression and the risk of AR may exist in centers that routinely transplant patients with higher risk of AR. Thus the risk/benefit of this strategy may be altered in these centers. We report a case of antibody-mediated rejection that followed reduction of immunosuppression for BKVN diagnosed more than 3 months after the onset of viremia. This rejection episode resulted in a greater decrease in graft function than the initial BKVN episode. Issues relevant to the management of these patients are discussed, including the need for improved immune monitoring assays to determine more accurately the balance between infection and rejection.

背景与目标： ：BK病毒性肾病（BKVN）被越来越多地认为是同种异体肾功能衰竭的主要原因。最近的报道表明，检测到持续的病毒血症后，免疫抑制的迅速降低可与病毒血症的消退相关，而急性排斥反应（AR）的风险最小。但是，这些经验通常发生在AR基线风险较低的中心。在常规移植AR风险较高的患者的中心中，过度免疫抑制和AR风险之间可能存在更好的平衡。因此，在这些中心可以改变这种策略的风险/利益。我们报告了一例抗体介导的排斥反应，随后在病毒血症发作后3个月内诊断为BKVN的免疫抑制降低。与最初的BKVN发作相比，该排斥发作导致移植物功能的下降更大。讨论了与这些患者的治疗有关的问题，包括需要改进免疫监测方法以更准确地确定感染和排斥反应之间的平衡。

BACKGROUND & AIMS: :Crystalized deposits of monosodium urate activate the Nod-like receptor protein 3 (NLRP3) inflammasome, resulting in kidney damage. The present study investigated whether the NLRP3 inflammasome is associated with the progression of hyperuricaemia and gouty nephropathy. Adult male patients were recruited at the Affiliated Baoan Hospital of Shenzhen and divided into three groups of 15 patients each: The control group, the hyperuricaemia group and the gouty nephropathy group. General characteristics and organ function indicators were also measured for each patient. NLRP3, apoptosis-associated speck like protein (ASC) and caspase-1 mRNA and protein expressions in peripheral blood mononuclear cells were detected. The expression of certain downstream inflammatory factors, including interleukin (IL)-1β and IL-18 were also assessed in plasma. The results demonstrated that the concentration of uric acid and creatinine were increased in the hyperuricaemia and gouty nephropathy groups compared with the control group. NLRP3, ASC and caspase-1 mRNA and protein expression, and IL-1β and IL-18 expression were increased in the hyperuricaemia and gouty nephropathy groups compared with the control group. In addition, ASC and caspase-1 mRNA and protein expression, and IL-1β expression were higher in the gouty nephropathy group compared with the hyperuricaemia group. In conclusion, the present results supported the hypothesis that the NLRP3 inflammasome signalling pathway is associated with gouty nephropathy leading to initiation of the inflammatory response and causing renal damage.

背景与目标： ：尿酸单钠的结晶沉积物会激活Nod样受体蛋白3（NLRP3）炎性小体，导致肾脏损害。本研究调查了NLRP3炎性体是否与高尿酸血症和痛风性肾病的进展有关。深圳市宝安附属医院招募成年男性患者，分为三组，每组15例：对照组，高尿酸血症组和痛风性肾病组。还测量了每位患者的一般特征和器官功能指标。检测外周血单个核细胞中的NLRP3，凋亡相关斑点样蛋白（ASC）和caspase-1 mRNA和蛋白表达。血浆中还评估了某些下游炎症因子的表达，包括白介素（IL）-1β和IL-18。结果表明，与对照组相比，高尿酸​​血症和痛风性肾病组的尿酸和肌酐浓度升高。与对照组相比，高尿酸​​血症和痛风性肾病组的NLRP3，ASC和caspase-1 mRNA和蛋白表达以及IL-1β和IL-18表达升高。此外，与高尿酸血症组相比，痛风性肾病组的ASC和caspase-1 mRNA和蛋白表达以及IL-1β表达更高。总之，本研究结果支持以下假设：NLRP3炎性体信号通路与痛风性肾病有关，从而导致炎症反应的开始并引起肾脏损害。

BACKGROUND & AIMS: :Fc receptor-like (FCRL) 4 is an immunoregulatory receptor expressed on a subpopulation of human memory B cells of mucosa-associated lymphoid tissue. Fc receptor function of FCRL4 was demonstrated by binding of IgA to FCRL4 following heat aggregation of the Ig. In this study, we demonstrate that FCRL4 recognizes J chain-linked systemic IgA in the absence of heat aggregation. We further demonstrate that mucosal secretory IgA is not recognized by FCRL4 and that systemic IgA binding can be competitively inhibited by recombinant secretory component protein. Finally, we provide evidence that primary FCRL4-bearing human memory B cells are constitutively bound to IgA. Our study provides a mechanism for the negative regulatory activity of FCRL4 on AgR-mediated B cell activation.

背景与目标： ：Fc受体样（FCRL）4是一种在与黏膜相关的淋巴组织的人类记忆B细胞亚群上表达的免疫调节受体。在Ig热聚集后，IgA与FCRL4的结合证明了FCRL4的Fc受体功能。在这项研究中，我们证明了FCRL4在不存在热聚集的情况下识别J链连接的全身IgA。我们进一步证明，粘膜分泌型IgA不被FCRL4识别，全身性IgA结合可被重组分泌成分蛋白竞争性抑制。最后，我们提供的证据表明，携带原代FCRL4的人类记忆B细胞与IgA组成性结合。我们的研究为FCRL4对AgR介导的B细胞活化的负调控活性提供了一种机制。

BACKGROUND & AIMS: :Suppression of rheumatoid factor (RF) production in rheumatoid arthritis (RA) has been variably attributed to the use of remittive agents per se or to clinical improvement associated with their use. There have been conflicting reports with regard to the influence of methotrexate (MTX) on serum RF levels in RA. We determined IgM-RF and IgA-RF levels in paired serum samples (obtained at study entry and completion) from RA patients enrolled in multicenter trials with the Cooperative Systematic Studies of Rheumatic Diseases program. After exclusion of the 14 IgM-RF-negative sera, there were samples from 30 MTX-treated patients and 52 placebo-treated patients. Changes in IgM-RF and IgA-RF levels were weakly associated with each other. Significant decreases in IgM-RF levels were observed in the MTX-treated patients, but not in the placebo group. These changes were most significant in the MTX-treated patients who improved clinically. There were significant decreases in IgA-RF levels at study completion among MTX-treated patients who had improved clinically and those who had not improved clinically, but not in the placebo group. The contributions of clinical improvement and MTX treatment to changes in serum IgM-RF and IgA-RF levels were examined using a logistic regression model. Changes in IgM-RF were strongly related to MTX treatment and, to a lesser extent, to clinical improvement; changes in IgA-RF were related only to MTX treatment. These results indicate that MTX treatment per se decreases both IgM-RF and IgA-RF levels, whereas clinical improvement correlates with decreased IgM-RF levels only.(ABSTRACT TRUNCATED AT 250 WORDS)

背景与目标： ：在类风湿关节炎（RA）中抑制类风湿因子（RF）的产生已被归因于使用释放剂本身或与使用它们相关的临床改善。关于甲氨蝶呤（MTX）对RA血清RF水平的影响，有相互矛盾的报道。我们通过风湿性疾病合作系统研究计划参加了多中心试验的RA患者的配对血清样本（在研究进入和完成时获得）中确定了IgM-RF和IgA-RF的水平。排除14种IgM-RF阴性血清后，有30名接受MTX治疗的患者和52名接受安慰剂治疗的患者的样本。 IgM-RF和IgA-RF水平的变化之间存在弱关联。在接受MTX治疗的患者中观察到IgM-RF水平显着降低，但在安慰剂组中未观察到。这些变化在经MTX治疗且临床上有所改善的患者中最为显着。在研究完成时，在临床上有所改善和在临床上没有改善的患者中，但在安慰剂组中，在研究结束时，IgA-RF水平显着降低。使用逻辑回归模型检查了临床改善和MTX治疗对血清IgM-RF和IgA-RF水平变化的贡献。 IgM-RF的变化与MTX治疗密切相关，在较小程度上与临床改善密切相关。 IgA-RF的变化仅与MTX治疗有关。这些结果表明，MTX治疗本身会降低IgM-RF和IgA-RF水平，而临床改善仅与IgM-RF水平降低相关（摘要截断为250个字）

BACKGROUND & AIMS: :The aim of the present study was to investigate the involvement of B cell‑activating factor (BAFF) in the pathogenesis of IgA nephropathy by activating the tumor necrosis factor receptor‑associated factor 6 (TRAF6)/NF‑κB signaling pathway in glomerular mesangial cells. For the clinical analysis, blood, urine and kidney tissue samples were collected from 58 patients diagnosed with primary IgA nephropathy by renal biopsy. For the in vitro study, glomerular mesangial cells were divided into five groups: Control (con)‑short hairpin RNA (shRNA) (control group); con‑shRNA + BAFF (20 ng/ml); con‑shRNA + BAFF + BAFF‑RFc chimera protein (500 µg/ml); TRAF6‑shRNA; and TRAF6‑shRNA + BAFF (20 ng/ml). For the in vivo experiments, 60 Sprague‑Dawley rats were randomly divided into four groups: Con‑small interfering RNA (siRNA) (control group); con‑siRNA + IgA (IgA nephropathy group), BAFF‑RFc chimera protein (2 µg/ml) + IgA, and TRAF6‑siRNA (0.2 µM) + IgA. Reverse transcription‑quantitative PCR was performed to evaluate the mRNA expression levels of TRAF6, connective tissue growth factor (CTGF), fibronectin (FN) and NF‑κBP65. Western blot analysis was used to detect the protein expression levels of TRAF6, FN, CTGF and phosphorylated‑NF‑κBP65 in glomerular mesangial cells and kidney tissues. The results revealed that plasma BAFF levels were positively correlated with the severity of pathological damage in patients with IgA nephropathy. In vitro, BAFF induced the mRNA and protein expression of TRAF6, CTGF, FN and NF‑κBP65 in glomerular mesangial cells. After the BAFF‑RFc chimera protein was added to inhibit the binding of BAFF and BAFF‑receptor (‑R), this effect was reduced. In vivo, inhibition of the effects of BAFF via injection with the BAFF‑R Fc chimera protein reduced kidney damage in rats suffering from IgA nephropathy. The effect on the expression of signaling pathway‑associated proteins was also alleviated. In conclusion, BAFF enhanced the expression of fibroblast factors in the kidneys by activating the TRAF6/NF‑κB signaling pathway.

背景与目标： ：本研究的目的是通过激活肾小球系膜中的肿瘤坏死因子受体相关因子6（TRAF6）/NF-κB信号通路，研究B细胞激活因子（BAFF）在IgA肾病发病机制中的参与细胞。为了进行临床分析，收集了58例经肾活检诊断为原发性IgA肾病的患者的血液，尿液和肾脏组织样本。对于体外研究，将肾小球系膜细胞分为五组：对照组（con）-短发夹RNA（shRNA）（对照组）；肾小球系膜细胞（shRNA）。 con‑shRNA BAFF（20 ng / ml）； con‑shRNA BAFF BAFF‑RFc嵌合蛋白（500 µg / ml）； TRAF6-shRNA；和TRAF6‑shRNA BAFF（20 ng / ml）。对于体内实验，将60只Sprague-Dawley大鼠随机分为四组：超小型干扰RNA（siRNA）（对照组）； con‑siRNA IgA（IgA肾病组），BAFF‑RFc嵌合蛋白（2 µg / ml）IgA和TRAF6‑siRNA（0.2 µM）IgA。进行逆转录定量PCR评估TRAF6，结缔组织生长因子（CTGF），纤连蛋白（FN）和NF-κBP65的mRNA表达水平。 Western blot分析用于检测肾小球系膜细胞和肾组织中TRAF6，FN，CTGF和磷酸化的NF-κBP65的蛋白表达水平。结果显示，血浆BAFF水平与IgA肾病患者的病理损害严重程度呈正相关。在体外，BAFF诱导肾小球系膜细胞中TRAF6，CTGF，FN和NF-κBP65的mRNA和蛋白表达。加入BAFF‑RFc嵌合蛋白以抑制BAFF和BAFF受体（‑R）结合后，这种作用减弱了。在体内，通过注射BAFF‑R Fc嵌合蛋白抑制BAFF的作用可减少IgA肾病大鼠的肾脏损害。也减轻了对信号通路相关蛋白表达的影响。总之，BAFF通过激活TRAF6 / NF‑κB信号通路增强了肾脏中成纤维细胞因子的表达。

BACKGROUND & AIMS: AIMS/HYPOTHESIS:Diabetic nephropathy, characterised by persistent proteinuria, hypertension and progressive kidney failure, affects a subset of susceptible individuals with diabetes. It is also a leading cause of end-stage renal disease (ESRD). Non-synonymous (ns) single nucleotide polymorphisms (SNPs) have been reported to contribute to genetic susceptibility in both monogenic disorders and common complex diseases. The objective of this study was to investigate whether nsSNPs are involved in susceptibility to diabetic nephropathy using a case-control design. METHODS:White type 1 diabetic patients with (cases) and without (controls) nephropathy from eight centres in the UK and Ireland were genotyped for a selected subset of nsSNPs using Illumina's GoldenGate BeadArray assay. A chi (2) test for trend, stratified by centre, was used to assess differences in genotype distribution between cases and controls. Genomic control was used to adjust for possible inflation of test statistics, and the False Discovery Rate method was used to account for multiple testing. RESULTS:We assessed 1,111 nsSNPs for association with diabetic nephropathy in 1,711 individuals with type 1 diabetes (894 cases, 817 controls). A number of SNPs demonstrated a significant difference in genotype distribution between groups before but not after correction for multiple testing. Furthermore, neither subgroup analysis (diabetic nephropathy with ESRD or diabetic nephropathy without ESRD) nor stratification by duration of diabetes revealed any significant differences between groups. CONCLUSIONS/INTERPRETATION:The nsSNPs investigated in this study do not appear to contribute significantly to the development of diabetic nephropathy in patients with type 1 diabetes.

背景与目标： 目的/假设：糖尿病性肾病的特征是持续性蛋白尿，高血压和进行性肾衰竭，影响了一部分易感糖尿病患者。它也是终末期肾病（ESRD）的主要原因。据报道，非同义（ns）单核苷酸多态性（SNP）有助于单基因疾病和常见复杂疾病的遗传易感性。这项研究的目的是调查病例对照设计是否nsSNPs参与糖尿病肾病的易感性。
方法：使用Illumina的GoldenGate BeadArray测定法，对来自英国和爱尔兰八个中心的患有（病例）和没有（对照）肾病的白人1型糖尿病患者进行基因分型，以筛选出选定的nsSNP子集。按中心分层的卡氏（2）趋势检验用于评估病例与对照之间基因型分布的差异。使用基因组控制来调整测试统计数据的可能膨胀，使用错误发现率方法解释多种测试。
结果：我们评估了1,111 nsSNP与1711例1型糖尿病患者（894例，817例对照）的糖尿病肾病相关性。许多SNPs在校正多个测试之前但没有校正后，各组之间的基因型分布存在显着差异。此外，亚组分析（伴有ESRD的糖尿病性肾病或未伴有ESRD的糖尿病性肾病）和糖尿病持续时间的分层均未显示各组之间的任何显着差异。
结论/解释：本研究中研究的nsSNPs似乎对1型糖尿病患者的糖尿病性肾病的发生没有显着贡献。

BACKGROUND & AIMS: :The incidence of diabetes mellitus (DM) has increased alarmingly over the last decades. Despite taking measures aimed at controlling hyperglycaemia and blood pressure, the rate of end-stage renal disease (ESRD) is continually growing. Upon increased amounts of advanced glycation end products (AGEs) and their correspondent receptors (RAGEs), AGE-RAGE axis is over-activated in DM, being the first step in the initiation and propagation of inflammatory cascades. Meanwhile, HMGB1, released from damaged cells in the diabetic kidneys, is the most notable ligand for the highly expressed toll-like receptors (TLRs) and RAGEs. TLRs play an indispensable role in the pathogenesis of diabetic nephropathy. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are hypoglycaemic agents acting on the renal proximal tubules to prevent glucose reabsorption and therefore increase urinary glucose excretion. Besides improving glycaemic control, these hypoglycaemic agents possess direct renoprotective properties. Here, therefore, we review the most recent findings regarding interrelationship between SGLT2 inhibitors and HMGB1-TLR4 axis.

背景与目标： 在过去的几十年中，糖尿病（DM）的发病率惊人地增加了。尽管采取了旨在控制高血糖和血压的措施，但终末期肾病（ESRD）的发病率仍在不断增长。随着高级糖基化终产物（AGEs）及其对应受体（RAGEs）数量的增加，在DM中AGE-RAGE轴被过度激活，这是引发和传播炎症级联反应的第一步。同时，从糖尿病肾脏受损细胞释放的HMGB1是高表达的Toll样受体（TLR）和RAGE的最显着配体。 TLR在糖尿病性肾病的发病机理中起着不可或缺的作用。葡萄糖钠共转运蛋白2（SGLT-2）抑制剂是降血糖药，作用在肾近端小管上，以防止葡萄糖重吸收并因此增加尿中葡萄糖的排泄。这些降血糖剂除了改善血糖控制外，还具有直接的肾脏保护特性。因此，在这里，我们回顾了有关SGLT2抑制剂和HMGB1-TLR4轴之间相互关系的最新发现。

BACKGROUND & AIMS: :Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.

背景与目标： ：糖尿病性肾病与氧化应激增加和肾脏组织缺氧密切相关。氧化应激增加导致肾脏耗氧量增加，导致肾脏组织缺氧。迄今为止，很难确定肾脏缺氧本身对肾病发展的作用。我们检验了以下假设：肾脏缺氧没有混杂因素，例如高血糖症或氧化应激升高，都会导致肾病。为了诱导肾脏缺氧，连续30天对大鼠施用二硝基苯酚（每天30 mg / kg体重，每天每公斤体重），这是一种线粒体解偶联剂，可增加耗氧量并引起肾脏缺氧。此后，确定肾小球滤过率，肾血流量，肾脏耗氧量，肾脏氧气张力，肾脏葡萄糖和糖原浓度，氧化应激指标，尿蛋白排泄和组织学发现，并将其与溶媒治疗对照组进行比较。二硝基苯酚不会影响动脉血压，肾血流量，肾小球滤过率，血糖或氧化应激指标，但会增加肾脏耗氧量，并降低皮质和髓质中葡萄糖和糖原的浓度，并导致肾内组织缺氧。此外，二硝基苯酚处理可增加尿蛋白排泄，肾脏波形蛋白表达和炎性细胞浸润。总之，线粒体耗氧量增加会导致肾脏缺氧和随后的肾病。重要的是，这些结果表明，在不混淆高血糖症或氧化应激的情况下，肾脏组织本身缺氧可能足以引发肾病的发展，因此证明了治疗肾脏疾病的新的介入目标。

BACKGROUND & AIMS: BACKGROUND:More and more studies demonstrated that genetic variation at C1GALT1 influences Gd-IgA1 level in IgAN. However, whether the expression of β1, 3-galactosyltransferase (β1, 3Gal-T) was influenced may provide insights into how Gd-IgA1 levels are controlled in IgAN. METHODS:Thirty IgAN patients diagnosed in Tianjin Medical University General Hospital from April to September 2018 and 30 healthy volunteers whose age and gender matched with patients were enrolled in this study. Total Gd-IgA1 levels in plasma were determined by ELISA and C1GALT1 levels were determined by RT-PCR. Four databases (PubMed, EMBASE, CNKI, WanFang Medical Network) were searched to identify eligible studies that evaluated a difference in the expression of C1GALT1 in IgAN patients compared with total controls (non-IgAN and health controls). The C1GALT1C1 expression levels, which was indispensable to β1, 3Gal-T of IgA1, was also been compared. RESULTS:Gd-IgA1 levels were remarkable higher in IgAN patients compared with healthy control. The expression levels of C1GALT1 gene were remarkably down-regulated in IgAN patients compared with healthy control. And the mRNA level of C1GALT1 was inversely correlated to Gd-IgA1 levels. In meta-analysis, six articles including 316 participants that analyzed the expression of β1, 3Gal-T were met inclusion criteria. There was no significant difference in the expression of C1GALT1 between IgAN patients compared with controls. And we found patients with IgAN had lower levels of C1GALT1 gene expression in the B cells compared to controls. The C1GALT1C1 levels in the IgAN patients were not different from the levels in the control group, which were unchanged no matter according to different ethnic population, different control group and different cell source. Two studies including 46 persons compared enzymatic activity of β1, 3Gal-T in B cells, and the result showed the β1, 3Gal-T activity was decreased in B cells. CONCLUSIONS:We found expression levels of C1GALT1 were remarkably downregulated in IgAN patients and negatively correlated with higher levels of Gd-IgA1. Subsequent meta-analysis validated the low expression and activity of β1, 3Gal-T in B cells in patients with IgAN. However, there was no apparent disparity in the aspect of C1GALT1C1 expression between IgAN and control groups.

背景与目标： 背景：越来越多的研究表明，C1GALT1的遗传变异会影响IgAN中的Gd-IgA1水平。但是，是否影响了β1、3-半乳糖基转移酶（β1、3Gal-T）的表达，可以提供有关如何在IgAN中控制Gd-IgA1水平的见解。
方法：纳入2018年4月至2018年9月在天津医科大学总医院诊断的30例IgAN患者和30名年龄和性别与患者相匹配的健康志愿者。通过ELISA测定血浆中总Gd-IgA1水平，通过RT-PCR测定C1GALT1水平。搜索四个数据库（PubMed，EMBASE，CNKI，万方医学网）以鉴定合格的研究，这些研究评估了IgAN患者与总对照（非IgAN和健康对照）相比C1GALT1表达的差异。还比较了IgA1的β1、3Gal-T不可缺少的C1GALT1C1表达水平。
结果：与健康对照组相比，IgAN患者的Gd-IgA1水平显着更高。与健康对照组相比，IgAN患者中C1GALT1基因的表达水平显着下调。 C1GALT1的mRNA水平与Gd-IgA1水平呈负相关。在荟萃分析中，符合纳入标准的6篇文章（包括316名参与者）分析了β1、3Gal-T的表达。与对照组相比，IgAN患者之间C1GALT1的表达没有显着差异。而且我们发现，与对照组相比，IgAN患者的B细胞中C1GALT1基因表达水平较低。 IgAN患者的C1GALT1C1水平与对照组无差异，无论根据不同的种族，不同的对照组和不同的细胞来源，C1GALT1C1水平均无变化。包括46人在内的两项研究比较了B细胞中β1、3Gal-T的酶活性，结果表明B细胞中β1、3Gal-T的酶活性降低。
结论：我们发现，IgAN患者中C1GALT1的表达水平显着下调，并且与Gd-IgA1的较高水平呈负相关。随后的荟萃分析验证了IgAN患者B细胞中β1、3Gal-T的低表达和活性。然而，在IgAN和对照组之间在C1GALT1C1表达方面没有明显的差异。

BACKGROUND & AIMS: :The Fc alpha/mu receptor (Fcα/μR, CD351) is a receptor that has dual specificity for IgA and IgM. Its second extracellular domain (EC2) has an Ig variable region-like structure and is predicted to be the ligand binding domain. EC2 is homologous to the first Ig-like domain (D1) of polymeric Ig receptor (pIgR) and has three complementarity-determining region (CDR)-like loops. A peptide that includes the CDR1-like loop region has been found to be responsible for IgA and IgM binding. However, whether the CDR2- and CDR3-like loops of EC2 contribute to ligand binding has remained unclear. In this work, we made three chimaeric receptors composed of the hFcα/μR backbone but having the CDR1-, CDR2- and CDR3-like loops of EC2 replaced by their counterpart loops from human pIgR D2, which itself does not bind IgA or IgM. Flow cytometry and confocal microscopy analysis showed that substitution of either the CDR1- or the CDR2-like loop abrogated IgA and IgM binding, indicating that both the CDR1- and the CDR2-like loops were important for ligand binding. In comparison, substitution of CDR3-like loop resulted in significant loss of IgM binding but has only a small negative effect on IgA binding. In addition, site-directed mutagenesis of the three CDR-like loops showed that residues Val29, Arg31, Asn54, Gln55, Glu98, Asn99 and Asn100 were involved in both IgA and IgM binding, and substitution of Glu98 within the CDR3-like loop increased IgA binding but decreased IgM binding.

背景与目标： ：Fcα/μ受体（Fcα/μR，CD351）是对IgA和IgM具有双重特异性的受体。它的第二个细胞外结构域（EC2）具有Ig可变区样结构，并被预测为配体结合结构域。 EC2与聚合Ig受体（pIgR）的第一个Ig样结构域（D1）同源，并具有三个互补决定区（CDR）样环。已经发现包括CDR1样环区的肽负责IgA和IgM结合。但是，尚不清楚EC2的CDR2和CDR3样环是否有助于配体结合。在这项工作中，我们制备了三个由hFcα/μR骨架组成的嵌合受体，但EC2的CDR1，CDR2和CDR3样环被来自人类pIgR D2的对应环所取代，后者本身不结合IgA或IgM。流式细胞术和共聚焦显微镜分析表明，CDR1-或CDR2-样环的取代消除了IgA和IgM的结合，表明CDR1-和CDR2-样环对配体结合都很重要。相比之下，CDR3样环的取代导致IgM结合的显着丧失，但对IgA结合的负面影响很小。此外，三个CDR样环的定点诱变表明残基Val29，Arg31，Asn54，Gln55，Glu98，Asn99和Asn100参与IgA和IgM的结合，并且在CDR3样环内的Glu98取代增加了。 IgA结合，但IgM结合降低。

BACKGROUND & AIMS: :We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m2 . After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m2 , a single-value index of the metabolites changed by -0.31 (95%CI -0.60 to -0.02; P  = .035), -0.08 (-12 to 0.29; P  = .43) and 0.01 (-0.21 to 0.19; P  = .913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (-0.17 to 0.43; P  = .40) and 0.35 (0.05-0.65; P  = .02) for atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m2 , suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated.

背景与目标： ：我们评估了阿曲生坦疗法对一组预定能反映糖尿病肾病患者线粒体功能的13种尿液代谢产物的作用。这项事后分析是使用RADAR研究期间收集的尿液样本进行的，这是一项随机，双盲，安慰剂对照试验，测试了阿特拉森坦对2型糖尿病和肾病患者白蛋白尿减少的影响。基线时，eGFR <60 mL / min / 1.73 m2的患者中，通过气相色谱质谱法定量的13种代谢物中有4种低于可检测水平，有6种减少。在eGFR <60 mL / min / 1.73 m2的患者中使用阿曲生坦治疗12周后，代谢物的单值指数变化了-0.31（95％CI -0.60至-0.02; P = .035），-0.08（在安慰剂中为-12至0.29; P = 0.43）和0.01（-0.21至0.19; P = 0.913），阿曲生坦分别为0.75和1.25 mg / d。与安慰剂相比，阿曲生坦0.75和1.25 mg / d的代谢物指数差异分别为0.13（-0.17至0.43； P = 0.40）和0.35（0.05-0.65； P = 0.02）。这些数据证实了2型糖尿病，肾病和eGFR <60 mL / min / 1.73 m2的患者线粒体功能障碍的先前发现，这表明阿曲生坦可以预防特定患者群体常见的线粒体功能障碍的发展。指出了未来使用阿曲生坦治疗更长的时间的研究。

BACKGROUND & AIMS: :Complement Factor H-Related protein 5 Nephropathy (CFHR5N) is an endemic hereditary renal disease in the island of Cyprus. Although only very recently recognized, it has provided insight into previously unknown genetic aspects of complement-mediated renal diseases and in fact it has contributed to the introduction of the new disease classification, 'C3 Glomerulopathy'. Herein, based on evidence from epidemiological, genetic, clinical and basic research studies, the hypothesis that CFHR5N could be protective from rickettsial infections is proposed. Confirming this hypothesis, could have significant implications for the study of Complement Factor- H Related Proteins (CFHRs) in renal diseases and rickettsial molecular microbiology.

背景与目标： ：补体因子H相关蛋白5肾病（CFHR5N）是塞浦路斯岛的地方性遗传性肾病。尽管它只是在最近才得到认可，但它提供了对补体介导的肾脏疾病以前未知的遗传学方面的见识，实际上，它为引入新的疾病分类“ C3肾小球病”做出了贡献。在此，基于流行病学，遗传学，临床和基础研究的证据，提出了CFHR5N可以保护立克次氏体感染的假说。证实这一假设，可能对肾脏疾病和and病分子微生物学中补体因子H相关蛋白（CFHRs）的研究具有重要意义。