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通讯作者:

邢昌赢,E-mail:cyxing62@126.com

中图分类号:R587.2

文献标识码:A

文章编号:1007-4368(2022)04-511-08

DOI:10.7655/NYDXBNS20220408

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目录contents

    摘要

    目的:探讨人类抗原R(human antigen R,HuR)在不同分期糖尿病肾病患者中的差异。方法:选取2014年1月— 2019年5月在南京医科大学第一附属医院经肾活检明确诊断的糖尿病肾病(diabetic kidney disease,DKD)患者165例以及肾脏恶性肿瘤患者16例。免疫组化法检测肾组织中HuR的表达水平。根据DKD病理分期进行分组,采用非参数检验比较各组患者HuR表达的差异。对HuR表达水平与临床指标的关系进行Spearman相关分析。结果:与肿瘤患者癌旁正常肾脏组织相比, HuR在DKD患者肾脏中表达增高,差异有统计学意义(P < 0.05)。HuR表达大多数位于肾小管上皮细胞,主要在细胞核内表达,部分在细胞质内表达。HuR在不同分期的DKD患者肾组织中表达有差异,其中Ⅱb期与Ⅲ期、Ⅱb期与Ⅳ期、Ⅲ期与Ⅳ期之间的差异有统计学意义(P < 0.05),而Ⅱa期与Ⅱb期之间差异无统计学意义。DKD患者HuR表达与年龄、血清肌酐、尿素氮、 血尿酸、C反应蛋白、甲状旁腺激素呈正相关,与估算的肾小球滤过率、血红蛋白、糖化血红蛋白、1,25羟维生素D3呈负相关。 结论:DKD病理分型在Ⅱb以上者HuR表达与病理分期呈正相关。HuR的表达与肾功能相关临床指标具有相关性。

    Abstract

    Objective:To explore the difference of human antigen R(HuR)expression in patients with diabetic kidney disease (DKD)at different stages. Methods:A total of 165 DKD patients diagnosed by renal biopsy admitted to the First Affiliated Hospital of Nanjing Medical University from January 2014 to May 2019 were enrolled,and 16 patients with renal carcinoma were included. The expression of HuR in the kidney was detected by immunohistochemistry. According to pathological classification of diabetic kidney disease,the expressions of HuR in each stage were compared by the Kruskal⁃Wallis test. Spearman’s rank correlation was performed for correlation analysis between HuR level and clinical factors. Results:The expression of HuR in the kidney was increased compared with paracancerous tissues of patients with renal carcinoma. HuR was mainly expressed in the nucleus,and partly in the cytoplasm. There were significant differences between diabetic kidney disease stage Ⅱb and stage Ⅲ,stage Ⅱb and stage Ⅳ,stage Ⅲ and stage Ⅳ(P < 0.05),but no difference between stage Ⅱa and stage Ⅱb was observed. HuR expression was positively correlated with age, serum creatinine,urea nitrogen,serum uric acid,C ⁃ reactive protein and parathyroid hormone(PTH),and negatively correlated with estimated glomerular filtration rate(eGFR),hemoglobin,glycosylated hemoglobin and 1,25 ⁃(OH)2 ⁃ vitamin D3. Conclusion:The expression of HuR is positively related to the severity of pathological stages(Ⅱb,Ⅲ,Ⅳ). The expression of HuR is correlated with clinical indicators of renal function.

    Keywords

    diabetic nephropathyHuRfibrosis

  • 在过去的几十年里糖尿病在全球范围内发病率大幅上升,糖尿病肾病(diabetic kidney disease, DKD)已经成为许多国家终末期肾病的主要原因[1-2]。 DKD的发病机制复杂多样,但肾脏纤维化包括肾小球硬化和肾小管间质纤维化是疾病进展到终末期肾脏病的共同通路[3]。越来越多的证据表明,上皮间质转分化(epithelial⁃mesenchymal transition,EMT) 在肾纤维化中起着至关重要的作用。EMT是一种表型变化,它会使正常细胞失去上皮特征转变为成纤维细胞[4-5]

  • 人类抗原R(human antigen R,HuR)是最具特征性的RNA结合蛋白之一,是一种约36kDa的蛋白质。它可以通过与3′⁃UTR中富含A或U的序列元件相互作用,参与调节mRNA的稳定性。HuR与EMT密切相关。TGF⁃β1/HuR反馈回路可以调节心脏成纤维细胞中的纤维化反应。有文献报道,DKD患者和大鼠肾组织中的HuR表达升高。此外,HuR与转录因子和细胞因子的3′⁃UTR结合,诱导EMT。而抑制HuR可能阻断高糖诱导的肾小管EMT,减轻DKD中的肾纤维化[6]。这些均提示HuR参与DKD的进程,HuR可能成为DKD肾脏纤维化程度的指标。但是,目前有关不同分期的DKD患者HuR表达差异的研究相对较少,因此,本研究选取2014年1月—2019年5月在南京医科大学第一附属医院经肾活检明确诊断的DKD患者165例,研究经肾脏病理明确的DKD不同病理分期患者肾组织中HuR表达差异。

  • 1 对象和方法

  • 1.1 对象

  • 选取2014年1月—2019年5月在南京医科大学第一附属医院经肾活检明确诊断DKD患者165例。排除标准:①年龄< 18岁;②急性肾损伤患者;③穿刺肾小球< 5个;④合并严重其他系统疾病和其他肾小球疾病患者。从肿瘤病灶0.5cm处收集相应的癌旁组织16例,并经病理证实为正常组织。本研究经南京医科大学第一附属医院伦理委员会批准(伦理审查号:2018⁃SR⁃250),所有研究对象均知情同意。

  • 1.2 方法

  • 1.2.1 临床数据

  • 肾活检时收集患者的以下临床资料:年龄、性别、血压、空腹血糖、糖化血红蛋白、血尿素氮、血清肌酐、中性粒细胞明胶酶相关脂质运载蛋白(neutrophil gelatinase⁃associated lipocalin,NGAL)、24h尿蛋白、甲状旁腺激素(parathyroid hormone,PTH)等。估算的肾小球滤过率(estimated glomerular filtration rate, eGFR)根据慢性肾脏疾病流行病学协作(CKD⁃EPI) 公式计算。

  • 肾脏标本由两名经验丰富的病理学家通过光学显微镜、免疫荧光和电子显微镜进行常规检查,每个患者肾脏穿刺标本肾小球个数≥5。依据HE染色、PAS染色、银染以及Masson等光学显微镜下的染色,再结合电镜结果进行DKD病理分期诊断。诊断标准如下[7]:Ⅰ期,光镜下无或有轻微病变,电镜示基底膜增厚(年龄≥9岁患者,基底膜增厚标准为男性基底膜厚度> 430nm,女性基底膜厚度> 395nm); Ⅱa期,出现轻微的系膜扩张(>25%所见系膜区); Ⅱb期,严重的系膜扩张(>25%所见系膜区);Ⅲ期,出现Kimmelstiel⁃Wilson结节(K⁃W结节);Ⅳ期,严重的肾小球硬化(>50%肾小球硬化)。

  • 1.2.2 免疫组化

  • 石蜡包埋组织切片2 μm,脱蜡后切片在柠檬酸盐缓冲液(pH6.0)中20min,并用磷酸盐缓冲液 (PBS)洗涤。在室温下用5%牛血清白蛋白封闭1h,切片与HuR抗体(1∶8 000,Santa Cruz公司,美国) 4℃孵育过夜。切片用PBS洗涤,然后与二抗在37℃孵育1h。然后切片用DAB染色2min,再用苏木精复染细胞核,最后脱水并固定。每个部分由显微镜随机拍摄8~10张照片,并由Image⁃Pro Plus计算。

  • 1.3 统计学方法

  • 应用SPSS 20.0统计软件进行统计学分析。计量资料进行正态性检验,符合正态分布资料的数据,以均数±标准差(x- ± s)表示,非正态分布计量资料采用中位数(四分位数)[MP25P75)]表示,采用非参数检验。低于检测值下限的数值被估算为各检测下限的的一半[8]。使用Spearman相关分析临床指标与HuR表达的相关性。两组间比较采用独立样本 t 检验,多组之间比较采用单因素方差分析。所有检验均以双侧P< 0.05为差异有统计学意义。

  • 2 结果

  • 2.1 患者基本资料

  • 共有165例患者被纳入本研究,其中男127例 (76.50%),女38例(23.50%),血清肌酐水平为 [111.50(84.05,175.95)]μmol/L,血红蛋白(111.44 ±2 5.22)g/L。患者24h尿蛋白、糖化血红蛋白、白蛋白等基线水平见表1。

  • 将165例患者依据病理诊断结果分为 Ⅱa期、Ⅱb期、Ⅲ期、Ⅳ期。其中Ⅱa期16例、Ⅱb期37例,Ⅲ期70例,Ⅳ期42例,癌旁组织作为正常对照组。单因素方差分析显示血清肌酐、尿素氮、 PTH和血清铁等在各分组之间差异有统计学意义 (表2)。

  • 表1 165例DKD患者临床资料

  • Table1 Clinical characteristics of 165DKD patients

  • 表2 不同病理分期DKD患者的临床资料

  • Table2 Clinical characteristics of DKD patients in different pathological stages

  • 2.2 不同病理分期患者的HuR表达有差异

  • 免疫组化结果显示,与正常对照组相比, HuR在DKD患者肾脏组织内表达增高,由图1可见HuR主要在肾小管上表达。通过半定量分析结果显示病理分期严重的患者HuR表达增高。 Ⅱb期与 Ⅲ 期、Ⅱb期与 Ⅳ 期、Ⅲ 期与Ⅳ期之间差异存在统计学意义(P< 0.05),而 Ⅱa期与 Ⅱb期之间差异无统计学意义 (图2)。

  • 2.3 HuR与患者临床数据的相关性

  • 如表3和图3所示,DKD患者HuR表达与血清肌酐、尿素氮、血尿酸、C反应蛋白、PTH呈正相关(P< 0.05),与eGFR、血红蛋白、糖化血红蛋白、1,25羟维生素D3呈负相关(P< 0.05)。

  • 3 讨论

  • HuR,一种反式作用的基因元件,是一种核糖核酸结合因子且富含腺嘌呤和尿嘧啶序列的基因元件。在多种肾脏疾病中,如代谢性酸中毒、缺血和纤维化,都出现了HuR表达的失调[2]。静息状态下, HuR主要位于细胞核内。在各种刺激下,HuR从细胞核出来进入细胞质,通过核糖核酸识别序列与靶mRNA 3′⁃UTR中的顺式作用元件结合,从而通过抑制mRNA降解和去甲基化来调节mRNA的稳定性[9]。在完成稳定mRNA的过程后,HuR从mRNA中释放出来,并迅速返回细胞核[10]。文献表明,HuR的核转录和HuR核质转运都是因炎症信号而被激活的,激活后可以发挥稳定炎症介质的作用[11-13]。 HuR参与了多种细胞过程的调节,包括细胞周期调节、应激反应、细胞凋亡和肿瘤进展[14-15]。研究发现HuR参与调控多种肿瘤细胞,如胆囊癌、结肠癌等的EMT进程[16-18]。近几年来HuR在肾小管上皮细胞中的作用备受关注。

  • 图1 HuR在不同分期DKD患者肾脏中的表达

  • Fig.1 Expression of HuR in kidney tissues of DKD patients in different stages

  • 图2 不同病理分期患者的HuR定量表达

  • Fig.2 Quantitative analysis of HuR expressions in dif⁃ ferent pathological stages

  • 表3 DKD患者HuR与临床指标的相关性

  • Table3 Correlation between HuR and clinical index⁃ es in DKD patients

  • EMT是一种上皮细胞逐渐失去细胞极性和细胞间黏附能力,与此同时获得成纤维细胞形态、迁移和侵袭特性的细胞程序。肾小管细胞可经EMT转化为肌成纤维细胞,激活的肌成纤维细胞可导致细胞外基质蛋白的过度沉积,是维持肾纤维化持续进展的关键因素。肾小管细胞中呈EMT分子特征的细胞数目与血清肌酐水平和肾间质损伤程度密切相关[19]。相应地,EMT作为动态且可逆的病理生理过程,阻断EMT进程的治疗策略可有效减轻肾脏纤维化[20-21]。基础研究证实抑制HuR可能阻断高糖诱导的肾小管EMT,减轻DKD中的肾纤维化。

  • 本研究发现,HuR在DKD患者肾组织中主要表达于肾小管上皮细胞核,并随着病理程度加重表达增加,进一步佐证了HuR在DKD疾病进展中发挥重要作用。与正常对照组相比,除了肾小管,HuR在肾小球内的表达也增高,尤其是在一些受损较严重的肾小球内,这与本课题组前期发现一致[22]。可见HuR在部分细胞的胞核胞浆均有表达,揭示了DKD标本中HuR的核质穿梭,这与以前的研究结果一致[6]。由于HuR的核质穿梭是瞬时发生的,在本研究中尚未观察到正在转移中的HuR。本研究重点关注了HuR在DKD中的表达,证实在DKD患者肾脏中HuR表达增高,并且在病理分型更严重的糖尿病患者肾脏中,HuR表达更高。众所周知,病理分型程度越严重,肾纤维化程度越重。这提示HuR在DKD肾纤维化中占有一定作用。本研究数据显示,伴随着HuR的升高,患者糖化血红蛋白也上升,两者呈正相关,而HuR表达与肌酐、尿素氮以及eGFR等反映肾脏功能的指标呈显著相关性。

  • 炎症也是糖尿病发展至终末期肾病,导致进行性肾组织纤维化的重要通路[23]。HuR参与了多种炎症性疾病[24-25],并可以调节自身免疫性疾病中的炎症因子。HuR还可以通过与白介素⁃1β、肿瘤坏死因子α等炎性细胞因子结合并稳定其转录来参与炎症过程[26]。本研究结果也显示HuR与炎症指标CRP呈正相关。机体内活性维生素D主要由肾脏产生,而肾脏也是影响维生素D代谢的重要器官。 1,25羟维生素D3通过胞浆内维生素D受体复合物发挥作用,维生素D受体的密度和功能会随着肾功能下降而降低[27]。并且既往研究证实维生素D具有抑制炎症因子表达的作用[28]。1,25羟维生素D3可以通过抑制Th1型细胞因子的产生抑制细胞免疫,缺乏1,25羟维生素D3会导致免疫调节功能受损[29],这可能从多角度解释本研究中HuR与1,25羟维生素D3呈负相关。1,25羟维生素D3水平低下使PTH mRNA水平升高,PTH合成增加[30]。这可能间接导致HuR与PTH呈负相关。

  • 图3 DKD患者HuR与临床指标的相关性

  • Fig.3 Correlation between HuR and clinical indexes in DKD patients

  • 综上所述,在DKD肾组织中HuR与DKD病理的严重程度与肾功能相关指标密切相关。因此, HuR可能成为值得关注的DKD治疗靶点。

  • 参考文献

    • [1] FU H,LIU S,BASTACKY S I,et al.Diabetic kidney dis⁃ eases revisited:a new perspective for a new era[J].Mol Metab,2019,30:250-263

    • [2] FEIGERLOVÁ E,BATTAGLIA ⁃HSU S F.Role of post ⁃ transcriptional regulation of mRNA stability in renal pathophysiology:focus on chronic kidney disease[J].FASEB J,2017,31(2):457-468

    • [3] HANG S,HUANG Q,CAI X,et al.Osthole ameliorates re⁃ nal fibrosis in mice by suppressing fibroblast activation and epithelial⁃mesenchymal transition[J].Front Physiol,2018,9:1650

    • [4] CAREW R M,WANG B,KANTHARIDIS P.The role of EMT in renal fibrosis[J].Cell Tissue Res,2012,347(1):103-116

    • [5] HILLS C E,SQUIRES P E.TGF⁃beta1⁃induced epithelial⁃ to⁃mesenchymal transition and therapeutic intervention in diabetic nephropathy[J].Am J Nephrol,2010,31(1):68-74

    • [6] SHI Q,LEE D Y,FÉLIERS D,et al.Interplay between RNA⁃binding protein HuR and Nox4 as a novel therapeu⁃ tic target in diabetic kidney disease[J].Mol Metab,2020,36:100968

    • [7] TERVAERT T,WMOOYAART A L,AMANN K,et al.Pathologic classification of diabetic nephropathy[J].J Am Soc Nephrol,2010,21(4):556-63

    • [8] WARE L B,KOYAMA T,ZHAO Z,et al.Biomarkers of lung epithelial injury and inflammation distinguish severe sepsis patients with acute respiratory distress syndrome [J].Crit Care,2013,17(5):R253

    • [9] SEUFERT L,BENZING T,IGNARSKI M,et al.RNAbinding proteins and their role in kidney disease[J].Nat Rev Nephrol,2022,18(3):153-170

    • [10] ROTHAMEL K,ARCOS S,KIM B,et al.ELAVL1 primar⁃ ily couples mRNA stability with the 3’UTRs of interferon⁃ stimulated genes[J].Cell Rep,2021,35(8):109178

    • [11] OSMA ⁃GARCIA I C,CAPITAN ⁃SOBRINO D,MOUYS⁃ SET M,et al.The RNA⁃binding protein HuR is required for maintenance of the germinal centre response[J].Nat Commun,2021,12(1):6556

    • [12] PAN H,STRICKLAND A,MADHU V,et al.RNA bind⁃ ing protein HuR regulates extracellular matrix gene ex⁃ pression and pH homeostasis independent of controlling HIF ⁃1alpha signaling in nucleus pulposus cells[J].Ma⁃ trix Biol,2019,77:23-40

    • [13] GOVINDAPPA P K,PATIL M,GARIKIPATI V N S,et al.Targeting exosome⁃associated human antigen R atten⁃ uates fibrosis and inflammation in diabetic heart[J].FASEB J,2020,34(2):2238-2251

    • [14] YANG C,KELAINI S,CAINES R,et al.RBPs play im⁃ portant roles in vascular endothelial dysfunction under di⁃ abetic conditions[J].Front Physiol,2018,9:1310

    • [15] PARHAM L R,WILLIAMS P A,CHATTERJI P,et al.RNA regulons are essential in intestinal homeostasis[J].Am J Physiol Gastrointest Liver Physiol,2019,316(1):G197-G204

    • [16] JIANG D,ZHANG Y,YANG L,et al.Long noncoding RNA HCG22 suppresses proliferation and metastasis of bladder cancer cells by regulation of PTBP1[J].J Cell Physiol,2020,235(2):1711-1722

    • [17] TAŞ i,HAN J,PARK S Y,et al.Physciosporin suppres⁃ ses the proliferation,motility and tumourigenesis of colorectal cancer cells[J].Phytomedicine,2019,56:10-20

    • [18] DUFIES M,GIULIANO S,AMBROSETTI D,et al.Suni⁃ tinib stimulates expression of VEGFC by tumor cells and promotes lymphangiogenesis in clear cell renal cell carci⁃ nomas[J].Cancer Res,2017,77(5):1212-1226

    • [19] KIMURA T,ISAKA Y,YOSHIMORI T.Autophagy and kidney inflammation[J].Autophagy,2017,13(6):997-1003

    • [20] CHEN H,YANG T,WANG M C,et al.Novel RAS inhibi⁃ tor 25⁃O ⁃methylalisol F attenuates epithelial ⁃to ⁃mesen⁃ chymal transition and tubulo⁃interstitial fibrosis by selec⁃ tively inhibiting TGF⁃beta⁃mediated Smad3 phosphoryla⁃ tion[J].Phytomedicine,2018,42:207-218

    • [21] LOVISA S.Epithelial⁃to⁃mesenchymal transition in fibro⁃ sis:concepts and targeting strategies[J].Front Pharma⁃ col,2021,12:737570

    • [22] LIU S,HUANG Z,TANG A,et al.Inhibition of RNAbinding protein HuR reduces glomerulosclerosis in exper⁃ imental nephritis[J].Clin Sci(Lond),2020,134(12):1433-1448

    • [23] ZHU X,JIANG L,LONG M,et al.Metabolic reprogram⁃ming and renal fibrosis[J].Front Med,2021,8:746920

    • [24] RAGURAMAN R,SHANMUGARAMA S,MEHTA M,et al.Drug delivery approaches for HuR ⁃ targeted therapy for lung cancer[J].Adv Drug Deliv Rev,2022,180:114068

    • [25] YU S,TRIPOD M,ATASOY U,et al.HuR plays a posi⁃ tive role to strengthen the signaling pathways of CD4 + T cell activation and Th17 cell differentiation[J].J Immu⁃ nol Res,2021,2021:9937243

    • [26] ZHANG F,CAI Z,LV H,et al.Multiple functions of HuR in urinary tumors[J].J Cancer Res Clin Oncol,2019,145(1):11-18

    • [27] 吴莉莉.2 型糖尿病患者血清 25(OH)D3、血管内皮生长因子水平与肾功能指标相关性[J].医学理论与实践,2021,34(10):1746-1748

    • [28] VIDOVIC N,FAID F,PANTOVIC A,et al.Vitamin D and cardio ⁃ metabolic biomarkers:small ⁃ scale compara⁃ tive study between Libyan migrants and resident women in Serbia[J].Libyan J Med,2019,14(1):1622364

    • [29] O′BRIEN M B,MCLOUGHLIN R M,ROCHE C,et al.Ef⁃ fect of IL ⁃ 8 haplotype on temporal profile in circulating concentrations of interleukin 8 and 25(OH)vitamin D in Holstein⁃Friesian calves[J].Vet Immunol Immunopathol,2021,238:110287

    • [30] DI FILIPPO L,ALLORA A,LOCATELLI M,et al.Hypo⁃ calcemia in COVID ⁃19 is associated with low vitamin D levels and impaired compensatory PTH response[J].En⁃ docrine,2021,74(2):219-225

  • 参考文献

    • [1] FU H,LIU S,BASTACKY S I,et al.Diabetic kidney dis⁃ eases revisited:a new perspective for a new era[J].Mol Metab,2019,30:250-263

    • [2] FEIGERLOVÁ E,BATTAGLIA ⁃HSU S F.Role of post ⁃ transcriptional regulation of mRNA stability in renal pathophysiology:focus on chronic kidney disease[J].FASEB J,2017,31(2):457-468

    • [3] HANG S,HUANG Q,CAI X,et al.Osthole ameliorates re⁃ nal fibrosis in mice by suppressing fibroblast activation and epithelial⁃mesenchymal transition[J].Front Physiol,2018,9:1650

    • [4] CAREW R M,WANG B,KANTHARIDIS P.The role of EMT in renal fibrosis[J].Cell Tissue Res,2012,347(1):103-116

    • [5] HILLS C E,SQUIRES P E.TGF⁃beta1⁃induced epithelial⁃ to⁃mesenchymal transition and therapeutic intervention in diabetic nephropathy[J].Am J Nephrol,2010,31(1):68-74

    • [6] SHI Q,LEE D Y,FÉLIERS D,et al.Interplay between RNA⁃binding protein HuR and Nox4 as a novel therapeu⁃ tic target in diabetic kidney disease[J].Mol Metab,2020,36:100968

    • [7] TERVAERT T,WMOOYAART A L,AMANN K,et al.Pathologic classification of diabetic nephropathy[J].J Am Soc Nephrol,2010,21(4):556-63

    • [8] WARE L B,KOYAMA T,ZHAO Z,et al.Biomarkers of lung epithelial injury and inflammation distinguish severe sepsis patients with acute respiratory distress syndrome [J].Crit Care,2013,17(5):R253

    • [9] SEUFERT L,BENZING T,IGNARSKI M,et al.RNAbinding proteins and their role in kidney disease[J].Nat Rev Nephrol,2022,18(3):153-170

    • [10] ROTHAMEL K,ARCOS S,KIM B,et al.ELAVL1 primar⁃ ily couples mRNA stability with the 3’UTRs of interferon⁃ stimulated genes[J].Cell Rep,2021,35(8):109178

    • [11] OSMA ⁃GARCIA I C,CAPITAN ⁃SOBRINO D,MOUYS⁃ SET M,et al.The RNA⁃binding protein HuR is required for maintenance of the germinal centre response[J].Nat Commun,2021,12(1):6556

    • [12] PAN H,STRICKLAND A,MADHU V,et al.RNA bind⁃ ing protein HuR regulates extracellular matrix gene ex⁃ pression and pH homeostasis independent of controlling HIF ⁃1alpha signaling in nucleus pulposus cells[J].Ma⁃ trix Biol,2019,77:23-40

    • [13] GOVINDAPPA P K,PATIL M,GARIKIPATI V N S,et al.Targeting exosome⁃associated human antigen R atten⁃ uates fibrosis and inflammation in diabetic heart[J].FASEB J,2020,34(2):2238-2251

    • [14] YANG C,KELAINI S,CAINES R,et al.RBPs play im⁃ portant roles in vascular endothelial dysfunction under di⁃ abetic conditions[J].Front Physiol,2018,9:1310

    • [15] PARHAM L R,WILLIAMS P A,CHATTERJI P,et al.RNA regulons are essential in intestinal homeostasis[J].Am J Physiol Gastrointest Liver Physiol,2019,316(1):G197-G204

    • [16] JIANG D,ZHANG Y,YANG L,et al.Long noncoding RNA HCG22 suppresses proliferation and metastasis of bladder cancer cells by regulation of PTBP1[J].J Cell Physiol,2020,235(2):1711-1722

    • [17] TAŞ i,HAN J,PARK S Y,et al.Physciosporin suppres⁃ ses the proliferation,motility and tumourigenesis of colorectal cancer cells[J].Phytomedicine,2019,56:10-20

    • [18] DUFIES M,GIULIANO S,AMBROSETTI D,et al.Suni⁃ tinib stimulates expression of VEGFC by tumor cells and promotes lymphangiogenesis in clear cell renal cell carci⁃ nomas[J].Cancer Res,2017,77(5):1212-1226

    • [19] KIMURA T,ISAKA Y,YOSHIMORI T.Autophagy and kidney inflammation[J].Autophagy,2017,13(6):997-1003

    • [20] CHEN H,YANG T,WANG M C,et al.Novel RAS inhibi⁃ tor 25⁃O ⁃methylalisol F attenuates epithelial ⁃to ⁃mesen⁃ chymal transition and tubulo⁃interstitial fibrosis by selec⁃ tively inhibiting TGF⁃beta⁃mediated Smad3 phosphoryla⁃ tion[J].Phytomedicine,2018,42:207-218

    • [21] LOVISA S.Epithelial⁃to⁃mesenchymal transition in fibro⁃ sis:concepts and targeting strategies[J].Front Pharma⁃ col,2021,12:737570

    • [22] LIU S,HUANG Z,TANG A,et al.Inhibition of RNAbinding protein HuR reduces glomerulosclerosis in exper⁃ imental nephritis[J].Clin Sci(Lond),2020,134(12):1433-1448

    • [23] ZHU X,JIANG L,LONG M,et al.Metabolic reprogram⁃ming and renal fibrosis[J].Front Med,2021,8:746920

    • [24] RAGURAMAN R,SHANMUGARAMA S,MEHTA M,et al.Drug delivery approaches for HuR ⁃ targeted therapy for lung cancer[J].Adv Drug Deliv Rev,2022,180:114068

    • [25] YU S,TRIPOD M,ATASOY U,et al.HuR plays a posi⁃ tive role to strengthen the signaling pathways of CD4 + T cell activation and Th17 cell differentiation[J].J Immu⁃ nol Res,2021,2021:9937243

    • [26] ZHANG F,CAI Z,LV H,et al.Multiple functions of HuR in urinary tumors[J].J Cancer Res Clin Oncol,2019,145(1):11-18

    • [27] 吴莉莉.2 型糖尿病患者血清 25(OH)D3、血管内皮生长因子水平与肾功能指标相关性[J].医学理论与实践,2021,34(10):1746-1748

    • [28] VIDOVIC N,FAID F,PANTOVIC A,et al.Vitamin D and cardio ⁃ metabolic biomarkers:small ⁃ scale compara⁃ tive study between Libyan migrants and resident women in Serbia[J].Libyan J Med,2019,14(1):1622364

    • [29] O′BRIEN M B,MCLOUGHLIN R M,ROCHE C,et al.Ef⁃ fect of IL ⁃ 8 haplotype on temporal profile in circulating concentrations of interleukin 8 and 25(OH)vitamin D in Holstein⁃Friesian calves[J].Vet Immunol Immunopathol,2021,238:110287

    • [30] DI FILIPPO L,ALLORA A,LOCATELLI M,et al.Hypo⁃ calcemia in COVID ⁃19 is associated with low vitamin D levels and impaired compensatory PTH response[J].En⁃ docrine,2021,74(2):219-225

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