Abnormal accumulation of oncometabolite fumarate drives susceptibility in fumarate hydratase-deficient renal cell carcinoma (FH-dRCC), but the precise mechanisms remain not fully understood. In this study, we demonstrate that high fumarate levels impair activation of ATR-CHK1 signaling in response to replication stress and DNA damage. Mechanistically, fumarate modifies RPA1, an essential factor for ATR-CHK1 activation through succination, a post-translational modification. Succination of RPA1 occurs mainly at cysteine residues 481 and 486, which reduces its binding affinity for single-stranded DNA (ssDNA). RPA1 succination leads to deficient recruitment of TOPBP1 to ssDNA, resulting in attenuated CHK1 activation and defective cell cycle arrest in response to DNA damage. Succinated RPA1 compromises homologous recombination-mediated DNA repair. Our findings establish that fumarate-induced succination of RPA1 impairs DNA repair and cell cycle control, promoting genomic instability in FH-dRCC. This work reveals a novel mechanism by which oncometabolites contribute to genomic instability.

糖尿病肾病(DKD)是糖尿病患者最常见的微血管并发症之一,也是终末期肾衰竭的主要原因,其发病机制比较复杂.大量实验证实表观遗传学机制包括组蛋白化学修饰与脂质代谢产物12/15脂氧化酶(12/15-LO)参与调控DKD的特征性病理生理过程,本综述将从他们之间的相互作用关系出发,进一步探讨DKD发病机制,为DKD的治疗提供新的研究方向.

It was a retrospective cohort study. Patients diagnosed with idiopathic membranous nephropathy (IMN) and received rituximab (RTX) alone for one course of treatment during hospitalization in the Department of Nephrology of the First Hospital of Jilin University from March 2020 to March 2022 were enrolled. The patients were divided into 1 g standard treatment group (once 1 g every 2 weeks for twice) and 375 mg/m 2 experimental treatment group (375 mg/m 2 once a week for 4 weeks) according to the different methods of drug administration, and the efficacy and safety of different doses of RTX in the treatment of IMN were compared between the two groups to provide a reference for optimizing the clinical treatment protocol. The patients were followed up regularly for more than 9 months after treatment and the data were complete. A total of 69 patients were included with age of (51.7±11.8) years old, and 46 males (66.7%). There were 31 patients in the 1 g standard treatment group and 38 patients in the 375 mg/m 2 experimental treatment group. The proportion of first-treatment patients in the 1 g standard treatment group was higher than that in the 375 mg/m 2 experimental treatment group (87.1% vs. 65.8%, χ2=4.174, P=0.041). There were no statistically significant differences in the general data, clinical characteristics and baseline laboratory parameters between the two groups (all P>0.05). At the end of 3 months of treatment, 22 patients (31.9%) experienced remission, including 9 patients (29.0%) in the 1 g standard treatment group and 13 patients (34.2%) in the 375 mg/m 2 experimental treatment group ( χ2=0.211, P=0.646). At 6 months, 30 patients (43.5%) experienced remission, including 12 patients (38.7%) in the 1 g standard treatment group and 18 patients (47.4%) in the 375 mg/m 2 experimental treatment group ( χ2=0.521, P=0.470). At 9 months, 38 patients (55.1%) achieved remission, including 18 patients (58.1%) in the 1 g standard treatment group and 20 patients (52.6%) in the 375 mg/m 2 experimental treatment group ( χ2=0.204, P=0.652). At 9 months, the 24 h urine protein of 1 g standard treatment group and 375 mg/m 2 experimental treatment group decreased by 7.93 (6.24, 8.46) g and 7.45 (5.66, 8.67) g (both P<0.05), respectively, and serum albumin increased by 16.4 (15.5, 17.5) g/L and 15.5 (9.0, 15.8) g/L (both P<0.05), respectively, from the baseline value. Kaplan-Meier survival analysis result showed that there was no significant difference in the time of phospholipase A2 receptor titer decreasing to <5 RU/ml between the two groups (Log-rank χ2=3.653, P=0.056). Twenty-three non-serious adverse events occurred in the 1 g standard treatment group, involving 16 patients, and 10 non-serious adverse events occurred in the 375 mg/m 2 experimental treatment group, involving 10 patients. There was better safety in the 375 mg/m 2 experimental treatment group than that in the 1 g standard treatment group ( Fisher value=8.593, P=0.015). Both 375 mg/m 2 regimen and 1 g regimen of RTX in IMN patients are effective in relieving proteinuria and elevating serum albumin. The 375 mg/m 2 regimen of RTX has a lower incidence of adverse events compared with the 1 g regimen.

人白细胞抗原G （HLA-G）是一种非经典的人主要组织相容性复合体（MHC）Ib分子，早期针对HLA-G的研究主要集中在妊娠期的免疫发育，其对母体和胎儿异种抗原的耐受性具有重要意义。近年来，越来越多的研究揭示了HLA-G在不同疾病中的作用和机制。HLA-G作为一种重要的免疫调节分子，在器官移植中的作用也有陆续报道。肾移植是终末期肾衰竭最有效的治疗选择，然而排斥反应是移植后主要的并发症，早期诊断急性、

12/15-脂氧合酶（lipoxygenase，LOX）参与多不饱和脂肪酸的代谢，其在糖尿病及其并发症糖尿病肾脏疾病（diabetic kidney disease，DKD）中的作用已经得到认识。动物实验表明，抑制或干扰12/15-LOX途径可以改善DKD动物模型的蛋白尿，延缓DKD进展。12/15-LOX还可以与血管紧张素Ⅱ、转化生长因子β及纤连蛋白等相互作用，促进DKD的发展。本文综述了12/15-LOX在炎症、胰岛素抵抗、DKD蛋白尿及肾脏纤维化等方面的研究进展。

沙库巴曲缬沙坦与达格列净可用于心力衰竭和糖尿病肾病的治疗，具有减少尿蛋白、保护肾脏功能的作用。我们应用沙库巴曲缬沙坦联合达格列净治疗肥胖相关性肾病合并重度心力衰竭1例，患者心功能明显改善，尿蛋白快速下降，随访期间肾功能、心力衰竭指数及心脏结构等指标稳定。

Immunoglobulin A nephropathy (lgAN) is a common primary glomerulonephritis, but paraneoplastic IgAN has been rarely reported. This current case report describes a 49-year-old male patient that was referred with proteinuria, oedema and hypoproteinaemia after lung cancer surgery and before the first cycle of chemotherapy. Renal biopsy confirmed lgAN. The patient received four cycles of chemotherapy (first cycle: pemetrexed + nedaplatin; second to fourth cycle: pemetrexed + carboplatin). The symptoms of IgAN were gradually relieved with additional cycles of chemotherapy. At the latest follow-up on 10 February 2020, there was no evidence of lung cancer recurrence and all symptoms of lgAN had disappeared. lgAN combined with lung adenocarcinoma is quite rare, which suggests that IgAN might be a paraneoplastic manifestation of lung adenocarcinoma.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and membranous nephropathy (MN) are two types of diseases that can both involve kidneys. In recent years, there are some reports about the concurrence of these two diseases. However, the precise mechanism, clinical course, and optimal treatment of patients with this unusual combination of renal diseases are little known. Previously reported cases of MN combined with AAV presented characteristics of both MN and crescentic glomerulonephritis, manifesting rapid disease progression and poor prognosis. Diagnosis and treatment are essential and challenging. Here, we report a case of AAV and MN in a 62 years old man, who was admitted to hospital due to edema, low-grade fever, and cough. The patient showed a different pathological feature from previous cases, with no crescent formation. By analyzing the diagnoses and potential pathogenesis, we considered MN was secondary to the present AAV and suspected the existence of other alternative mechanisms. Also, we applied a new therapy, glucocorticoid with mizoribine. After one-year follow-up, this treatment is feasible, safe, and leads to a clinical improvement for AAV combined with MN. In this case, two diseases overlapped, and the laboratory analysis and pathology are both required to ensure diagnostic accuracy. The principal aim of this case report is to highlight the diagnostic challenge and distinct treatment in the simultaneous occurrence of AAV combined with MN.

目的:探讨12/15-脂氧化酶(12/15-LO)基因敲除(12/15-LOKO)对高脂饮食(HFD)诱导的肥胖小鼠肾组织的保护作用,阐明其在肾脏疾病进展中的作用.方法:将16只12/15-LOKO小鼠和16只WT小鼠各自随机分为HFD组和标准饮食喂养(SFD)组,每组8只.HFD组小鼠给予HFD喂养,SFD组小鼠给予SFD喂养(即WT+HFD、WT+SFD、LOKO+HFD和LOKO+SFD组).分别于喂养1、8和14周收集小鼠24 h尿液,14周后采血并处死小鼠.检测各组小鼠体质量、双肾质量和后腿胫骨长,分别在第1、8和14周时代谢笼收集各组小鼠24 h尿液,检测尿蛋白水平、尿蛋白肌酐比(PCR)和尿微量白蛋白肌酐比(ACR).葡萄糖耐量试验(GTT)检测各组小鼠空腹血糖水平,实时定量逆转录PCR(RT-qPCR)法检测各组小鼠肾皮质组织中adiponectin、肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)、单核细胞趋化蛋白1(MCP-1)、纤溶酶原激活物抑制剂1(PAI-1)和转化生长因子 β1(TGF-β1)mRNA表达水平,ELASA法检则各组小鼠血清中adiponectin、TNF-α、IL-6、血管紧张素Ⅱ(AngⅡ)和胰岛素水平.PAS染色观察小鼠肾组织病理形态表现,Western blotting法检测各组小鼠肾皮质组织中TGF-β1和PAI-1蛋白表达情况.结果:HFD组小鼠体质量明显高于SFD组(P<0.01),肾脏质量和肾小球面积明显大于SFD组(P<0.01);WT+HFD组小鼠ACR和PCR高于WT+SFD组(P<0.05);与LOKO+HFD组比较,WT+HFD组小鼠空腹血糖水平升高(P<0.05),WT+HFD组小鼠肾皮质组织中TNF-α、IL-6和MCP-1 mRNA表达水平明显高于WT+SFD组(P<0.05);与LOKO+HFD组比较,WT+HFD组小鼠肾皮质组织中IL-6和MCP-1 mRNA表达水平明显升高(P<0.05),adiponectin mRNA表达水平降低(P<0.05).WT+HFD组小鼠肾皮质组织中PAI-1和TGF-β1 mRNA表达水平高于WT+SFD组(P<0.05),LOKO+HFD组小鼠肾皮质中PAI-1和TGF-β1 mRNA表达水平明显低于WT+HFD组(P<0.01).结论:12/15-LOKO有利于改善肥胖小鼠胰岛素抵抗、蛋白尿水平和肾小球肥大程度,其机制可能与抑制TNF-α和IL-6等炎症因子在肾组织中的表达、影响PAI-1和TGF-β1 mRNA的表达、从而发挥肾脏保护作用有关.

钠-葡萄糖共转运蛋白2（SGLT2）抑制剂是一类通过抑制近端小管重吸收葡萄糖发挥药效的新型降糖药。临床试验结果表明该类药物不仅可降低心血管疾病的发生率，还能改善糖尿病合并慢性肾脏病患者的肾脏转归，为2型糖尿病患者肾脏保护治疗提供了新的选择。SGLT2抑制剂的肾脏保护作用机制尚未明了，现有的研究结果提示除降血糖外，SGLT2抑制剂还可通过降低体重、血压、血尿酸及改善肾小球高滤过等发挥保护肾功能的作用。我们综述了SGLT2抑制剂的药物种类，阐述了SGLT2抑制剂可能的作用机制、不良反应及其在糖尿病肾病领域的临床应用进展。

Transforming growth factor-β1 (TGF-β)-induced fibrotic and inflammatory genes in renal mesangial cells (MCs) play important roles in glomerular dysfunction associated with diabetic nephropathy (DN). TGF-β regulates gene expression in MCs by altering key chromatin histone modifications at target gene promoters. However, the role of the repressive histone H3 lysine 27 trimethylation (H3K27me3) modification is unclear. Here we show that TGF-β reduces H3K27me3 at the Ctgf, Serpine1, and Ccl2 gene promoters in rat MCs (RMCs) and reciprocally up-regulates the expression of these pro-fibrotic and inflammatory genes. In parallel, TGF-β down-regulates Enhancer of Zeste homolog 2 (Ezh2), an H3K27me3 methyltransferase, and decreases its recruitment at Ctgf and Ccl2 but not Serpine1 promoters. Ezh2 knockdown with siRNAs enhances TGF-β–induced expression of these genes, supporting its repressive function. Mechanistically, Ezh2 down-regulation is mediated by TGF-β–induced microRNA, miR-101b, which targets Ezh2 3′-UTR. TGF-β also up-regulates Jmjd3 and Utx in RMCs, suggesting a key role for these H3K27me3 demethylases in H3K27me3 inhibition. In RMCs, Utx knockdown inhibits hypertrophy, a key event in glomerular dysfunction. The H3K27me3 regulators are similarly altered in human and mouse MCs. High glucose inhibits Ezh2 and increases miR-101b in a TGF-β–dependent manner. Furthermore, in kidneys from rodent models of DN, fibrotic genes, miR-101b, and H3K27me3 demethylases are up-regulated, whereas Ezh2 protein levels as well as enrichment of Ezh2 and H3K27me3 at target genes are decreased, demonstrating in vivo relevance. These results suggest that H3K27me3 inhibition by TGF-β via dysregulation of related histone-modifying enzymes and miRNAs augments pathological genes mediating glomerular mesangial dysfunction and DN.

Objective To investigate the effects of 12-lipoxygenase（12-LO）and angiotensinⅡ（AngⅡ）on the CIP/KIP family of cyclin-dependent kinase inhibitors（CKIs）p21,p27 and p57 related to cell hypertrophy.Methods Mesangial cells were treated with high glucose for 24hours and 48 hours respectively.12（S）-hydroxyeicosa-

Objective:To investigate the clinical characteristics,diagnosis and treatment of 1case of renal damage caused by aortic valve infective endocarditis(IE),and to review the literatures about diagnosis and treatment of renal damage caused by IE.Methods:Early diagnosis was performed with cardiac ultrasound and renal biopsy,and the patient with IE-induced renal damage was treated with lowering urinary protein and anti-infection,at the same time,aortic valve replacement and valvular vegetations dissection were performed in time.Results:The patient recovered well,and the urine protein level remained at 0.4-1.0g/24 h,and the renal function and glomerular filtration rate remained normal.Conclusion:In the treatment of IE associated renal damage,active and effective antimicrobial therapy and valve replacement to remove the infection are the most important.

The aim of the present study was to examine the impacts and mechanisms of 12‑lipoxygenase (12‑LO) and its metabolites on the acetylation and methylation of histone‑3‑lysine (H3K) in the p21 gene. Rat mesangial cells (MCs) were selected for use in the present study. A chromatin immunoprecipitation assay, reverse transcription‑quantitative polymerase chain reaction analysis and a luciferase assay were used to detect transcriptional activities, the acetylation (Ac) of H3K (H3KAc), p21 promoter methylation (Me) and the transcription regions induced by 12 (S)‑hydroxyeicosatetraenoic acid (HETE). The cells were transfected to induce the overexpression of p300 to examine changes in 12 (S)‑HETE‑associated p21 regulation and epigenetic modifications. 12 (S)‑HETE enhanced p21 transcriptional activity and mRNA expression. In the promoter regions, P1 and P2, and the T1 transcription region, 12 (S)‑HETE induced significant H3K9 Ac and H3K4 Me1 epigenetic modifications, however, no changes were observed in the T2 region. By contrast, 12 (S)‑HETE treatment markedly prevented H3K9Me3 at the p21 promoter, suggesting that complex Me was involved in 12 (S)‑HETE‑associated p21 regulation. Furthermore, the overexpression of p300 markedly enhanced basal and 12 (S)‑HETE‑associated p21 transcriptional regulation in the MCs. 12 (S)‑HETE treatment also induced histone acetyltransferase p300 occupancy in the p21 promoter, and reduced the nuclear expression and occupancy of lysine‑specific demethylase (LSD1) in the p21 promoter. 12 (S)‑HETE induced p300 occupancy, and reduced the nuclear expression and occupancy of LSD1 in the p21 promoter. Therefore, enhanced H3K9Ac and H3K4Me1 in the p21 promoter and transcription regions, and decreased H3K9Me3 in the p21 promoter increased the expression of p21.

AIM:A wealth of studies have demonstrated that abnormal cellular lipid metabolism plays an important role in prostate cancer (PCa) development. Therefore, manipulating lipid metabolism is a potential PCa therapy strategy. In this study, our goal is to investigate the role of farnesoid X receptor (FXR) in regulating the proliferation and lipid metabolism of human PCa cells following its ligand chenodexycholic acid (CDCA) treatment.METHODS:Oil Red O was used to stain lipid contents in PCa cells, and siRNA knockdown was performed to deplete FXR expression. To study the cell proliferation when treated by CDCA or FXR knockdown, cell counting kit 8 (CCK8) was adopted to evaluate tumor cell growth. Western blot was used for protein analysis.RESULTS:Our data suggest that activation of FXR by CDCA reduces lipid accumulation and significantly inhibits cells proliferation in prostate tumor cells. Instead, CDCA treatment doesn't affect normal prostate epithelial RWPE-1 cells growth in vitro. FXR activation decreases mRNA and protein levels of sterol regulatory element binding protein 1 (SREBP1) and some other key regulators involved in lipid metabolism. Depletion of FXR by siRNA attenuates the inhibitory effects.CONCLUSION:Our study indicates that activation of FXR inhibits lipid metabolism via SREBP1 pathway and further suppresses prostate tumor growth in vitro.

Direct ligand exchange kinetics between hydrophilic molecules and quantum dots(QDs) was investigated. Meanwhile, pyrene was exploited as probe to detect the efficiency of the ligand exchange reaction between octadecylamine-coated QDs(ODA-QDs) and different ligands[ligand 1: NH2G3-OH, ligand 2: G4.5-PEG5-FA5, ligand 3: (COOH)2G3-OH or ligand 4: G4.5-PEG1-FA1]. It was indicated that water-soluble QDs exhibit the same fluorescence and absorption spectra as ODA-QDs when they were dissolved in chloroform. Furthermore, the cellular experiments demonstrated that the folic acid(FA) targeting poly(amidoamine)(PAMAM) modified QD conjugates could be used as molecular targeting sensing systems for nanoparticle probes.

AIMSEpigenetic mechanisms, including histone post-translational modifications and DNA methylation, are implicated in the pathogenesis of diabetic nephropathy (DN), but the mediators are not well known. Moreover, although dyslipidemia contributes to DN, epigenetic changes triggered by lipids are unclear. In diabetes, increased expression of 12/15-lipoxygenase (12/15-LO) enhances oxidized lipids such as 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which promote oxidant stress, glomerular and mesangial cell (MC) dysfunction, and fibrosis, and mediate the actions of profibrotic growth factors. We hypothesized that 12/15-LO and its oxidized lipid products can regulate epigenetic mechanisms mediating profibrotic gene expression related to DN.RESULTS12(S)-HETE increased profibrotic gene expression and enrichment of permissive histone lysine modifications at their promoters in MCs. 12(S)-HETE also increased protein levels of SET7, a histone H3 lysine 4 methyltransferase, and promoted its nuclear translocation and enrichment at profibrotic gene promoters. Furthermore, SET7 (Setd7) gene silencing inhibited 12(S)-HETE-induced profibrotic gene expression. 12/15-LO (Alox15) gene silencing or genetic knockout inhibited transforming growth factor-β1 (TGF-β1)-induced expression of Setd7 and profibrotic genes and histone modifications in MCs. Furthermore, 12/15-LO knockout in mice ameliorated key features of DN and abrogated increases in renal SET7 and profibrotic genes. Additionally, 12/15-LO siRNAs in vivo blocked increases in renal SET7 and profibrotic genes in diabetic mice.INNOVATION AND CONCLUSIONThese novel results demonstrate for the first time that 12/15-LO-derived oxidized lipids regulate histone modifications associated with profibrotic gene expression in MCs, and 12/15-LO can mediate similar actions of TGF-β1 and diabetes. Targeting 12/15-LO might be a useful strategy to inhibit key epigenetic mechanisms involved in DN.

OBJECTIVE:Inconsistent results regarding the association between sodium intake and the risk of chronic kidney disease (CKD) have been reported. Thus, we conducted a meta-analysis to summarize the evidence from epidemiological studies of sodium with the risk of CKD.METHODS:Pertinent studies were identified by searching of PubMed and Web of Science. The random effect model was used to combine the results. Meta-regression and subgroups analyses were used to explore potential sources of between-study heterogeneity. Publication bias was estimated using Egger's regression asymmetry test.RESULTS:Finally, 9 articles involving 5638 CKD cases were included in this meta-analysis. Pooled results suggested that highest sodium intake level versus lowest level was significantly associated with the risk of CKD [summary relative risk (RR) = 1.088, 95% CI = 1.009-1.193, I(2) = 78.1%], especially among Europe [summary RR = 1.097, 95% CI = 1.009-1.205], but not in the America. The association was also found in the prospective studies [summary RR = 1.096, 95% CI = 1.007-1.192], but not in the cross-sectional studies. No evidence of significant publication bias was found.CONCLUSIONS:Higher sodium intake might increase the risk of CKD.

目的：探讨Klotho基因对糖尿病肾病大鼠肾脏保护作用的机制。方法取2月龄Wistar大鼠，腹腔注射 STZ诱导产生糖尿病，2 w后检测大鼠尿微量白蛋白增高证明糖尿病肾病（ DN）大鼠模型制备成功，另取18只正常大鼠腹腔注射等量柠檬酸缓冲液作为对照组（ Con 组）。将54只DN模型大鼠随机分成DN组、Ad组和Klotho组，Klotho组每隔2 w大鼠尾静脉注射含Klotho基因病毒3×108 PFU，Ad组注射等量不含Klotho基因的病毒，Con组和DN组注射等体积生理盐水。四组大鼠均至第4、8、16周处死，取肾组织。病理观察肾脏形态学变化，免疫组化观察Klotho蛋白和PAI-1的表达与分布；RT-PCR检测基因 Klotho、TGF-β1、p15、p21、p27、PAI-1 mRNA 在肾组织的表达，Quantity one 图像分析软件分析其表达量差异。结果免疫组化检测结果显示，与Con组对比，4、8、16w时，DN组和Ad组大鼠肾小球、肾小管及肾间质内Klotho蛋白表达量减少，而 Klotho组大鼠肾脏Klotho蛋白表达量变化不明显，与Con组接近；与Con 组相比，DN组和Ad组 PAI-1蛋白表达量增加，Klotho组的PAI-1蛋白表达量变化不明显，接近Con组。 RT-PCR结果显示，Klotho、TGF-β1、p15、p21、p27、PAI-1基因PCR产物与预期扩增产物大小一致，与Con组对比，在4、8、16 w时DN组和Ad组的Klotho mRNA表达量明显减少（P＝0．010～0．001），Klotho 组 Klotho mRNA 表达量变化不明显，但高于 DN组和 Ad组（P＝0．002～0．001）。DN组和Ad组TGF-β1、 p15、p21、p27、PAI-1 mRNA 表达量明显高于 Con组（P＝0．041～0．002），Klotho组变化不明显，接近 Con组，但低于DN组和Ad组（P＝0．048～0．002）。结论 Klotho基因通过下调TGF-β1、PAI-1、p15、p21、p27基因的表达而实现对糖尿病大鼠肾脏的保护作用。