2019, Vol. 14
2. 复旦大学附属中山医院泌尿外科, 上海市器官移植重点实验室, 上海 200032;
3. 复旦大学附属华山医院肾脏科, 上海 200040
2. Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China;
3. Department of Nephrology, Huashan Hospital, Fudan University, Shanghai 200040, China
乙型肝炎病毒(hepatitis B virus，HBV)属于嗜肝DNA病毒科，基因组全长约3.2 kb，是感染人的最小DNA病毒。迄今为止，全球约有2.5亿人感染了HBV[1]。当HBV感染者血清中的乙型肝炎表面抗原(hepatitis B surface antigen, HBsAg)持续存在超过6个月，即为慢性感染。慢性乙型肝炎患者罹患终末期肝病(包括肝硬化和肝癌)的风险大大增加[2]。一般认为，HBV感染的主要靶器官为肝脏。但流行病学研究显示，慢性乙型肝炎患者罹患慢性肾病和肾癌的风险也显著增加[3-5]。虽然慢性乙型肝炎相关性肾炎主要由免疫复合物(如HBsAg和抗-HBs复合物)沉积所致[6]，但许多研究已发现HBV感染标记[如HBsAg、乙型肝炎核心抗原(hepatitis B core antigen，HBcAg)、HBV RNA和DNA]存在于慢性乙型肝炎患者的肾脏细胞[7-10]，特别是近来有证据显示HBV功能性受体钠离子/牛磺胆酸共转运蛋白(Na+/taurocholate cotransporting polypeptide，NTCP)和支持HBV RNA转录的转录因子均在肾脏中表达[11-12]。因此，对于肾脏是否为HBV感染、表达和复制的另一靶器官，值得进一步探讨。
目前，用于治疗慢性乙型肝炎的药物包括α干扰素、聚乙二醇化α干扰素和核苷(酸)类似物，但它们都不能清除共价闭合环状DNA(covalently closed circular DNA，cccDNA)而无法达到病毒学治愈的目标[13]。因此，功能性治愈是当前慢性乙型肝炎治疗的目标，主要指标是HBsAg消失[13]。但当前的药物治疗极少能达到使HBsAg消失的目标(干扰素治疗3%~7%，核苷(酸)类似物治疗每年约1%)[13]。这也提示HBV可能潜伏在其他器官中。若肾脏是HBV感染、表达和复制的另一靶器官，HBV与肾脏细胞的相互作用、肾脏的抗病毒免疫反应将是全新研究领域。此外，现有治疗药物在肾脏内的抗病毒效应也值得评估。本文就HBV在肝脏内建立感染的决定因素、感染肾脏的可能性及乙型肝炎相关性肾炎的诊断和治疗进行简要综述。
1 HBV感染和复制HBV为包膜病毒，其包膜含有大(large，L)、中(middle，M)和小(small，S)3种表面蛋白，合称为HBsAg，其中由226个氨基酸(amino acid，aa)组成的S蛋白丰度最高。目前认为S蛋白为4次跨膜蛋白，其99~169位氨基酸位于第2和第3个跨膜区且暴露在病毒表面，因包含多个能诱生中和性抗体的线性和构型表位而被称作抗原环(antigenic loop，AGL)，M蛋白在S蛋白N端多出55个氨基酸的PreS2区，而L蛋白则在S蛋白N端多出108或119个氨基酸的PreS1区和PreS2区。M蛋白的功能未知，L蛋白PreS1区第2位甘氨酸豆蔻酰化(myristoylation)对L蛋白与NTCP的结合至关重要[14-15]。HBV先通过AGL与肝细胞表面肝素硫酸蛋白多糖(heparin sulfate proteoglycans，HSPG)结合，使病毒在肝细胞表面富集[16-17]，再通过PreS1 N端第2~48位氨基酸与NTCP结合介导HBV进入肝细胞[15, 18]。随后，病毒脱去包膜，释放核衣壳(nucleocapsid)，后者通过微管运输到细胞核，再脱壳将包裹的松弛环状DNA(relaxed circular DNA，rcDNA)释放入核。rcDNA可能借助细胞内的DNA修复系统而转化成cccDNA[19]。cccDNA包含2个增强子、4个启动子等转录调控元件[20]，一些肝细胞转录因子识别和结合这些调控元件而招募细胞的RNA聚合酶Ⅱ等转录复合物[21]。RNA聚合酶Ⅱ以cccDNA为模板转录出4组不同长度(3.5 kb、2.4 kb、2.1 kb和0.7 kb)的病毒RNA。3.5 kb前基因组RNA(pregenomic RNA，pgRNA)编码核心蛋白和聚合酶。聚合酶顺式结合pgRNA 5′端茎环结构(ε)并与核心蛋白二聚体及细胞因子(如Hsp90等)一起包装形成核衣壳。与此同时，聚合酶以pgRNA为模板将第1个脱氧核苷酸(dT)共价连接至聚合酶TP区第63位酪氨酸(该过程称为蛋白引发)[22]，从而起始病毒DNA复制。在核衣壳内，聚合酶依次以pgRNA为模板，通过反转录形成负链DNA，再降解pgRNA，并以负链DNA为模板合成正链DNA。3.5 kb的前C区RNA(precore RNA，pcRNA)编码乙型肝炎e抗原(hepatitis B e antigen, HBeAg)。2.4 kb和2.1 kb mRNA分别指导翻译L和M/S包膜蛋白。成熟的核衣壳被L、M和S包膜蛋白包裹形成完整的病毒颗粒，后者通过多囊泡体相关途径分泌出胞[23-25]。S包膜蛋白也以亚病毒颗粒的形式大量释放，其血中的浓度是完整病毒颗粒的1 000~10 000倍，是HBsAg的主要来源。
2 HBV感染人肝脏的决定因素HBV的嗜肝性由诸多因素决定。首先，暴露于HBV表面的L蛋白PreS1区与肝细胞表面的NTCP特异性作用是关键。最近，不同种属NTCP与PreS1结合能力测定及表达人NTCP的不同种属肝细胞的HBV易感性检测实验提供了重要证据。尽管来自人、小鼠、大鼠、狗、猪和猕猴的NTCP高度同源，但猕猴NTCP第157~165位氨基酸不同于人NTCP，导致PreS1多肽不能结合猕猴NTCP及HBV不能感染猕猴肝细胞[26]。小鼠NTCP虽然能结合Pres1多肽，但不介导HBV感染小鼠肝细胞，这主要是小鼠与人NTCP第84~87位氨基酸序列差异所致[15, 18]。通过腺相关病毒(adeno-associated virus，AAV)载体将人NTCP基因导入小鼠、大鼠、狗、猪和猕猴原代肝细胞，促使这些细胞表达人NTCP。HBV攻毒实验发现只有表达了人NTCP的猪和猕猴原代肝细胞建立了感染，而小鼠、大鼠、狗的原代肝细胞不能被感染[26]。如果将稳定表达人NTCP的小鼠肝细胞系与人HepG2细胞融合，这样的融合细胞却能支持HBV感染[27]。这些结果提示，除了NTCP，还有其他宿主因子对HBV建立感染至关重要。
肝细胞表达的肝富集转录因子结合cccDNA的增强子和启动子而促使HBV RNA转录是HBV嗜肝性的另一个重要因素。通过启动子活性检测以及点突变和缺失突变、转录调控序列与转录因子结合的凝胶迁移等实验发现，HNF4α、HNF3和RxRα/PPARα等是促使HBV RNA转录的关键转录因子[28-31]。非肝来源的NIH 3T3细胞不支持HBV转录和复制，但若将HNF4α或RxRα/PPARα与含1.3倍体HBV基因组表达质粒共转染该细胞，通过RNA/DNA印迹法证明了HBV RNA转录和DNA复制[28]。经尾静脉高压水动力注射将HBV表达质粒导入小鼠(如BALB/c和C57BL/6品系)肝脏可起始病毒复制，因此小鼠肝细胞包含支持HBV转录所需的转录因子[32]。但表达人NTCP的小鼠或小鼠原代肝细胞仍不能被HBV感染[27, 33]，提示从HBV侵入肝脏到cccDNA形成的某些环节在正常小鼠肝细胞内无法完成，其中可能的关键宿主因子还有待鉴定和研究。
3 肾脏具备HBV感染和复制的因素众多研究通过免疫组织化学、原位HBV RNA和DNA杂交等技术发现了HBV感染标记(如HBsAg、HBcAg、HBV RNA和DNA)存在于慢性乙型肝炎患者的肾小球内皮细胞、系膜细胞和肾小管上皮细胞[7-10]。这些肾脏细胞内的HBV标记可能是细胞吞噬血液中的病毒颗粒(或与抗体形成复合物)所致，也可能由整合在染色体上的HBV DNA所编码，或HBV感染这些肾脏细胞所致。HBV RNA和DNA阳性提示肾脏细胞能支持HBV转录和DNA复制。提取肾组织总DNA进行DNA印迹法，发现大部分HBV DNA显著长于3.2 kb，提示HBV DNA整合于宿主细胞染色体，也有少部分HBV DNA为复制中间体[34]。但这些研究缺少严谨的分子生物学实验以检测驱动HBV复制的天然模板——cccDNA，因此HBV是否在肾脏建立感染还有待证实。
用含1.2或1.3倍HBV基因组的质粒构建转基因C57BL/6小鼠，转基因鼠的肝脏和肾脏都高表达前基因组RNA和PreS/S mRNA[35-36]，这些病毒RNA再编码病毒复制和组装所需的核心蛋白、聚合酶、包膜蛋白等，通过DNA印迹法等技术证明HBV在转基因鼠肝脏和肾脏复制[35, 36]。本研究团队曾构建了整合HBV单倍体基因组的转基因小鼠[37]，虽然该系小鼠无HBV颗粒产生，但肝和肾小管上皮细胞都表达了HBsAg和核心蛋白[37]，通过蛋白免疫印迹和组织化学技术发现肝细胞富集的转录因子如HNF4、HNF3、HNF1、RxRα/PPARα等在肾脏表达[12, 38-41]。这些证据表明，肾脏提供了支持HBV RNA转录和DNA复制的必要因素。此外，用HBV表达质粒转染HEK-293人胚肾细胞起始HBV转录和复制，提取细胞总DNA，DNA印迹法检测发现该细胞支持cccDNA形成[42]，提示肾脏细胞可提供必需的宿主因子，促使HBV核衣壳入核及将rcDNA修复成cccDNA。
作为HBV低亲合力受体的HSPG(如Glypican 5)[16-17]在肝脏和肾脏(尤其是肾小管上皮细胞)均表达[43-44]。通过免疫组织化学技术发现，作为HBV高亲合力受体的NTCP在人肝脏和肾小管上皮细胞高表达(数据来源于蛋白定位数据库https://www.proteinatlas.org)。通过蛋白免疫印迹技术发现，NTCP在小鼠肝脏、肾脏和胰脏表达[11]。这些数据提示，人肾脏因表达NTCP而可能成为HBV感染的另一重要靶器官。
4 乙型肝炎相关性肾炎Combes于1971年最先在1例膜性肾病患者的肾活检标本中发现HBsAg沉积在肾小球基底膜上[45]。乙型肝炎相关性肾病主要包括乙型肝炎相关膜性肾病和乙型肝炎相关膜增生性肾小球肾炎[6]，还包括乙型肝炎相关性冷球蛋白血症的肾损害及在我国尚无报道的乙型肝炎相关性结节性多动脉炎。我国于1989年将乙型肝炎相关性肾病命名为HBV相关性肾小球肾炎。
目前，乙型肝炎相关性肾炎的诊断依据包括：①血清HBV标记阳性；②患肾病或肾炎并除外其他肾小球疾病；③肾小球中有一种或多种HBV抗原沉积；④肾脏病理改变，绝大多数为膜性肾病，少数为膜增生性肾炎和系膜增生性肾炎。根据2008年中华医学会儿科学分会肾脏病学组指南，乙型肝炎相关性肾炎的确诊标准为：同时具备上述第①、②和③条；同时具备上述第①、②条依据，且第④条依据中为膜性肾病；个别患者具备上述第②、③条依据，血清HBV标记阴性也可确诊。仅具备第①和②条但不具备③时，不能进行诊断。
肾活检病例中，血清HBsAg阳性比例约为6.8%(复旦大学附属华山医院2017—2018年统计数据)，与人群中HBV感染率相当。约7.6%的血清HBsAg阳性患者肾组织中至少一种HBV抗原阳性，按以上诊断标准可诊断为乙型肝炎相关性肾炎。
但现行诊断标准并非十全十美。例如，肾组织活检HBV阳性并不能完全等同于HBV感染就是肾炎的病因；而肾组织中HBV抗原阴性，也不能完全排除其作为肾炎的病因。在临床实践中，仅根据肾小球中滞留的HBV标记进行乙型肝炎相关性肾炎的诊断尚存在假阳性或假阴性，还需更多证据来辅助诊断。例如，通过抗病毒治疗使血清HBV抗原和病毒DNA拷贝数下降，如果肾病获得缓解则支持乙型肝炎相关性肾炎的诊断，如果肾病并无改善则可能不支持该诊断。此外，一些生物标记可提高乙型肝炎相关性肾炎诊断的特异性。最近，多项研究表明，磷脂酶A2受体(phospholipase A2 receptor，PLA2R)的抗体是特发性膜性肾病的有效标记，可用作HBV抗原-抗体沉积合并原发性膜性肾病与HBV抗原-抗体沉积所致膜性肾病的鉴别诊断[46-50]。
乙型肝炎相关性肾炎治疗以抗病毒治疗为主[6]。儿童首选干扰素，成人则多选择核苷类抗病毒药物，不主张盲目使用免疫抑制剂。
5 乙型肝炎与肾移植肾移植术后移植肾的功能和长期存活率与供、受体的HBV感染和复制情况密切相关。肾移植受者需长期服用免疫抑制剂，如果存在HBV感染因素，将对移植肾的功能产生重要影响。一项随访10年的研究表明，移植肾的长期存活率在HBV感染的受者中比无HBV感染受者中明显降低，HBV感染受者移植肾的丢失风险增加近4倍[51]。Chen等回顾了322例术前抗-HBc阳性/HBsAg阴性的肾移植受者，术后发现HBV活化率为4.7%[52]。另一项类似研究随访了631例受者，术前91.4%受者抗-HBsAg阳性；随访中位时间为151个月时，HBV活化率为6.7%；所有受者在未接受预防治疗的情况下抗-HBs效价稳定，仅2例出现HBV活化[53]。这些研究表明，在接受免疫抑制剂治疗时肾移植受者HBV活化率与受者体内抗-HBs效价呈负相关。若供体存在HBV感染，针对肾移植受者的HBV感染干预措施不同。若供体HBsAg阳性，HBsAg阳性受体需接受抗病毒(如恩替卡韦)治疗。若供体HBsAg/抗-HBc阳性且受体HBsAg抗体效价＞10 IU/L，则受者移植后不需接受治疗；若受者HBsAg抗体效价＜10 IU/L，则需HBV疫苗再次免疫、HBV免疫球蛋白中和病毒或核苷类似物抗病毒治疗[54]。目前，肾移植术后HBV是否潜伏在移植肾内仍未知，尚需进一步证实。
6 结语肾脏细胞内的HBV抗原可能改变细胞的生理和生化功能而导致肾脏功能受损。用HBV表达质粒转染肾脏细胞(如肾小管上皮细胞和肾小球间质细胞)发现HBx调节细胞凋亡[55-60]。在84%的乙型肝炎相关肾小球肾炎患者中，HBx的反式调控区发生突变[61]。本研究团队曾发现，表达HBsAg的HBV转基因鼠中血清补体C3降低，而肾组织补体C3升高[37]；类似改变也在HBsAg阳性乙型肝炎患者中发现，且补体C3在肾脏沉积与肾脏损伤呈正相关[62]。因此，研究和区分肾脏细胞内HBV标记的来源非常重要，针对不同来源，采取的主要治疗措施可能不同。若肾脏细胞内HBV标记来自病毒颗粒内吞或HBV感染，降低病毒载量的抗病毒治疗就显得更为重要；若标记来自HBV基因组整合，目前尚处于研发阶段的靶向病毒抗原的免疫治疗(如抗体治疗[63-65]和嵌合抗原受体T细胞免疫治疗[66-67])可能具有重要的应用前景。
乙型肝炎患者血中HBsAg浓度可高达300 μg/mL。过量的HBsAg封闭中和性抗体，除导致病毒逃逸外，还促使免疫复合物沉积于肾小球基底膜。最近多项证据表明HBsAg还干扰宿主抗病毒免疫反应[68-73]。因此，尚处于研发阶段的靶向HBsAg的抗体治疗或抑制HBsAg分泌并促进其在细胞内降解的化合物治疗[74]有望改善慢性乙型肝炎患者的肝脏和肾脏功能。
| [1] |
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013[J]. Lancet, 2015, 386(10003): 1546-1555.
[DOI]
|
| [2] |
Trépo C, Chan HL, Lok A. Hepatitis B virus infection[J]. Lancet, 2014, 384(9959): 2053-2063.
[DOI]
|
| [3] |
Chen YC, Su YC, Li CY, Hung SK. 13-year nationwide cohort study of chronic kidney disease risk among treatment-naive patients with chronic hepatitis B in Taiwan[J]. BMC Nephrol, 2015, 16: 110.
[DOI]
|
| [4] |
Hong YS, Ryu S, Chang Y, Cainzos-Achirica M, Kwon MJ, Zhao D, Shafi T, Lazo M, Pastor-Barriuso R, Shin H, Cho J, Guallar E. Hepatitis B virus infection and development of chronic kidney disease: a cohort study[J]. BMC Nephrol, 2018, 19(1): 353.
[DOI]
|
| [5] |
Lin YS, Yeh CC, Lin YC, Su CT, Sung FC, Chang SN, Liu YR, Su FH. Kidney cancer linked to chronic hepatitis in the Asia-Pacific: A population-based analysis[J]. Am J Nephrol, 2017, 45(1): 22-31.
[DOI]
|
| [6] |
Kupin WL. Viral-associated GN: Hepatitis B and other viral infections[J]. Clin J Am Soc Nephrol, 2017, 12(9): 1529-1533.
[DOI]
|
| [7] |
Chen L, Wu C, Fan X, Gao J, Yin H, Wang T, Wu J, Wen SW. Replication and infectivity of hepatitis B virus in HBV-related glomerulonephritis[J]. Int J Infect Dis, 2009, 13(3): 394-398.
[DOI]
|
| [8] |
Dejean A, Lugassy C, Zafrani S, Tiollais P, Brechot C. Detection of hepatitis B virus DNA in pancreas, kidney and skin of two human carriers of the virus[J]. J Gen Virol, 1984, 65(Pt 3): 651-655.
[DOI]
|
| [9] |
He XY, Fang LJ, Zhang YE, Sheng FY, Zhang XR, Guo MY. In situ hybridization of hepatitis B DNA in hepatitis B-associated glomerulonephritis[J]. Pediatr Nephrol, 1998, 12(2): 117-120.
[DOI]
|
| [10] |
Lai KN, Ho RT, Tam JS, Lai FM. Detection of hepatitis B virus DNA and RNA in kidneys of HBV related glomerulonephritis[J]. Kidney Int, 1996, 50(6): 1965-1977.
[DOI]
|
| [11] |
Ferdek PE, Jakubowska MA, Gerasimenko JV, Gerasimenko OV, Petersen OH. Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium-driven bile uptake[J]. J Physiol, 2016, 594(21): 6147-6164.
[DOI]
|
| [12] |
Lau HH, Ng NHJ, Loo LSW, Jasmen JB, Teo AKK. The molecular functions of hepatocyte nuclear factors-In and beyond the liver[J]. J Hepatol, 2018, 68(5): 1033-1048.
[DOI]
|
| [13] |
Zeisel MB, Lucifora J, Mason WS, Sureau C, Beck J, Levrero M, Kann M, Knolle PA, Benkirane M, Durantel D, Michel ML, Autran B, Cosset FL, Strick-Marchand H, Trépo C, Kao JH, Carrat F, Lacombe K, Schinazi RF, Barré-Sinoussi F, Delfraissy JF, Zoulim F. Towards an HBV cure: state-of-the-art and unresolved questions-report of the ANRS workshop on HBV cure[J]. Gut, 2015, 64(8): 1314-1326.
[DOI]
|
| [14] |
Urban S, Bartenschlager R, Kubitz R, Zoulim F. Strategies to inhibit entry of HBV and HDV into hepatocytes[J]. Gastroenterology, 2014, 147(1): 48-64.
[DOI]
|
| [15] |
Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, Huang Y, Qi Y, Peng B, Wang H, Fu L, Song M, Chen P, Gao W, Ren B, Sun Y, Cai T, Feng X, Sui J, Li W. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus[J]. Elife, 2012, 1: e00049.
[DOI]
|
| [16] |
Sureau C, Salisse J. A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus a-determinant[J]. Hepatology, 2013, 57(3): 985-994.
[DOI]
|
| [17] |
Verrier ER, Colpitts CC, Bach C, Heydmann L, Weiss A, Renaud M, Durand SC, Habersetzer F, Durantel D, Abou-Jaoudé G, López Ledesma MM, Felmlee DJ, Soumillon M, Croonenborghs T, Pochet N, Nassal M, Schuster C, Brino L, Sureau C, Zeisel MB, Baumert TF. A targeted functional RNA interference screen uncovers glypican 5 as an entry factor for hepatitis B and D viruses[J]. Hepatology, 2016, 63(1): 35-48.
[DOI]
|
| [18] |
Ni Y, Lempp FA, Mehrle S, Nkongolo S, Kaufman C, Fälth M, Stindt J, Königer C, Nassal M, Kubitz R, Sültmann H, Urban S. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes[J]. Gastroenterology, 2014, 146(4): 1070-1083.
[DOI]
|
| [19] |
Nassal M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B[J]. Gut, 2015, 64(12): 1972-1984.
[DOI]
|
| [20] |
Moolla N, Kew M, Arbuthnot P. Regulatory elements of hepatitis B virus transcription[J]. J Viral Hepat, 2002, 9(5): 323-331.
[DOI]
|
| [21] |
Kim DH, Kang HS, Kim KH. Roles of hepatocyte nuclear factors in hepatitis B virus infection[J]. World J Gastroenterol, 2016, 22(31): 7017-7029.
[DOI]
|
| [22] |
Nassal M. Hepatitis B viruses: reverse transcription a different way[J]. Virus Res, 2008, 134(1-2): 235-249.
[DOI]
|
| [23] |
Kian Chua P, Lin MH, Shih C. Potent inhibition of human Hepatitis B virus replication by a host factor Vps4[J]. Virology, 2006, 354(1): 1-6.
[DOI]
|
| [24] |
Lambert C, Döring T, Prange R. Hepatitis B virus maturation is sensitive to functional inhibition of ESCRT-Ⅲ, Vps4, and gamma 2-adaptin[J]. J Virol, 2007, 81(17): 9050-9060.
[DOI]
|
| [25] |
Watanabe T, Sorensen EM, Naito A, Schott M, Kim S, Ahlquist P. Involvement of host cellular multivesicular body functions in hepatitis B virus budding[J]. Proc Natl Acad Sci USA, 2007, 104(24): 10205-10210.
[DOI]
|
| [26] |
Lempp FA, Wiedtke E, Qu B, Roques P, Chemin I, Vondran FWR, Le Grand R, Grimm D, Urban S. Sodium taurocholate cotransporting polypeptide is the limiting host factor of hepatitis B virus infection in macaque and pig hepatocytes[J]. Hepatology, 2017, 66(3): 703-716.
[DOI]
|
| [27] |
Lempp FA, Mutz P, Lipps C, Wirth D, Bartenschlager R, Urban S. Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor[J]. J Hepatol, 2016, 64(3): 556-564.
[DOI]
|
| [28] |
Tang H, McLachlan A. Transcriptional regulation of hepatitis B virus by nuclear hormone receptors is a critical determinant of viral tropism[J]. Proc Natl Acad Sci USA, 2001, 98(4): 1841-1846.
[DOI]
|
| [29] |
Raney AK, Johnson JL, Palmer CN, McLachlan A. Members of the nuclear receptor superfamily regulate transcription from the hepatitis B virus nucleocapsid promoter[J]. J Virol, 1997, 71(2): 1058-1071.
[DOI]
|
| [30] |
Tang H, Banks KE, Anderson AL, McLachlan A. Hepatitis B virus transcription and replication[J]. Drug News Perspect, 2001, 14(6): 325-334.
[URI]
|
| [31] |
McFadden VC, Shalaby RE, Iram S, Oropeza CE, Landolfi JA, Lyubimov AV, Maienschein-Cline M, Green SJ, Kaestner KH, McLachlan A. Hepatic deficiency of the pioneer transcription factor FoxA restricts hepatitis B virus biosynthesis by the developmental regulation of viral DNA methylation[J]. PLoS Pathog, 2017, 13(2): e1006239.
[DOI]
|
| [32] |
Yang PL, Althage A, Chung J, Chisari FV. Hydrodynamic injection of viral DNA: a mouse model of acute hepatitis B virus infection[J]. Proc Natl Acad Sci USA, 2002, 99(21): 13825-13830.
[DOI]
|
| [33] |
He W, Ren B, Mao F, Jing Z, Li Y, Liu Y, Peng B, Yan H, Qi Y, Sun Y, Guo JT, Sui J, Wang F, Li W. Hepatitis D virus infection of mice expressing human sodium taurocholate co-transporting polypeptide[J]. PLoS Pathog, 2015, 11(4): e1004840.
[DOI]
|
| [34] |
Zhang YE, Ma XL, Fang LJ, Lin SY, Wu ZL, Gu JR. The existence and significance of hepatitis B virus DNA in glomerulonephritis[J]. Nephrology, 1996, 2(2): 119-125.
[DOI]
|
| [35] |
Araki K, Miyazaki J, Hino O, Tomita N, Chisaka O, Matsubara K, Yamamura K. Expression and replication of hepatitis B virus genome in transgenic mice[J]. Proc Natl Acad Sci USA, 1989, 86(1): 207-211.
[DOI]
|
| [36] |
Guidotti LG, Matzke B, Schaller H, Chisari FV. High-level hepatitis B virus replication in transgenic mice[J]. J Virol, 1995, 69(10): 6158-6169.
[DOI]
|
| [37] |
Ren J, Wang L, Chen Z, Ma ZM, Zhu HG, Yang DL, Li XY, Wang BI, Fei J, Wang ZG, Wen YM. Gene expression profile of transgenic mouse kidney reveals pathogenesis of hepatitis B virus associated nephropathy[J]. J Med Virol, 2006, 78(5): 551-560.
[DOI]
|
| [38] |
Kolatsi-Joannou M, Bingham C, Ellard S, Bulman MP, Allen LI, Hattersley AT, Woolf AS. Hepatocyte nuclear factor-1beta: a new kindred with renal cysts and diabetes and gene expression in normal human development[J]. J Am Soc Nephrol, 2001, 12(10): 2175-2180.
|
| [39] |
Harries LW, Ellard S, Stride A, Morgan NG, Hattersley AT. Isomers of the TCF1 gene encoding hepatocyte nuclear factor-1 alpha show differential expression in the pancreas and define the relationship between mutation position and clinical phenotype in monogenic diabetes[J]. Hum Mol Genet, 2006, 15(14): 2216-2224.
[DOI]
|
| [40] |
Drewes T, Senkel S, Holewa B, Ryffel GU. Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes[J]. Mol Cell Biol, 1996, 16(3): 925-931.
[DOI]
|
| [41] |
Portilla D, Dai G, McClure T, Bates L, Kurten R, Megyesi J, Price P, Li S. Alterations of PPARalpha and its coactivator PGC-1 in cisplatin-induced acute renal failure[J]. Kidney Int, 2002, 62(4): 1208-1218.
[DOI]
|
| [42] |
Gao W, Hu J. Formation of hepatitis B virus covalently closed circular DNA: removal of genome-linked protein[J]. J Virol, 2007, 81(12): 6164-6174.
[DOI]
|
| [43] |
Saunders S, Paine-Saunders S, Lander AD. Expression of the cell surface proteoglycan glypican-5 is developmentally regulated in kidney, limb, and brain[J]. Dev Biol, 1997, 190(1): 78-93.
[DOI]
|
| [44] |
Murata K. Acidic glycosaminoglycans in human kidney tissue[J]. Clin Chim Acta, 1975, 63(2): 157-169.
[DOI]
|
| [45] |
Combes B, Shorey J, Barrera A, Stastny P, Eigenbrodt EH, Hull AR, Carter NW. Glomerulonephritis with deposition of Australia antigen-antibody complexes in glomerular basement membrane[J]. Lancet, 1971, 2(7718): 234-237.
[DOI]
|
| [46] |
Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy[J]. N Engl J Med, 2009, 361(1): 11-21.
[DOI]
|
| [47] |
Larsen CP, Messias NC, Silva FG, Messias E, Walker PD. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies[J]. Mod Pathol, 2013, 26(5): 709-715.
[DOI]
|
| [48] |
Debiec H, Ronco P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy[J]. N Engl J Med, 2011, 364(7): 689-690.
[DOI]
|
| [49] |
Francis JM, Beck LH Jr, Salant DJ. Membranous nephropathy: a journey from bench to bedside[J]. Am J Kidney Dis, 2016, 68(1): 138-147.
[DOI]
|
| [50] |
Dong HR, Wang YY, Cheng XH, Wang GQ, Sun LJ, Cheng H, Chen YP. Retrospective study of phospholipase A2 receptor and IgG subclasses in glomerular deposits in Chinese patients with membranous nephropathy[J]. PLoS One, 2016, 11(5): e0156263.
[DOI]
|
| [51] |
Ng C, Danguilan R, Pamugas G, Que E. Outcomes of renal allograft recipients with hepatitis B from January 2000 to December 2010[J]. Transplant Proc, 2018, 50(10): 3242-3248.
[DOI]
|
| [52] |
Chen GD, Gu JL, Qiu J, Chen LZ. Outcomes and risk factors for hepatitis B virus (HBV) reactivation after kidney transplantation in occult HBV carriers[J]. Transpl Infect Dis, 2013, 15(3): 300-305.
[DOI]
|
| [53] |
Querido S, Weigert A, Adragão T, Rodrigues L, Jorge C, Bruges M, Machado D. Risk of hepatitis B reactivation in hepatitis B surface antigen seronegative and core antibody seropositive kidney transplant recipients[J]. Transpl Infect Dis, 2019, 21(1): e13009.
[DOI]
|
| [54] |
Veroux M, Ardita V, Corona D, Giaquinta A, Ekser B, Sinagra N, Zerbo D, Patanè M, Gozzo C, Veroux P. Kidney transplantation from donors with hepatitis B[J]. Med Sci Monit, 2016, 22: 1427-1434.
[DOI]
|
| [55] |
Han W, Luo M, He M, Zhu Y, Zhong Y, Ding H, Hu G, Liu L, Chen Q, Lu Y. HBx gene transfection affects the cycle of primary renal tubular epithelial cells through regulating cyclin expression[J]. Mol Med Rep, 2018, 18(2): 1947-1954.
[DOI]
|
| [56] |
He P, Zhang B, Liu D, Bian X, Li D, Wang Y, Sun G, Zhou G. Hepatitis B virus X protein modulates apoptosis in NRK-52E cells and activates Fas/FasL through the MLK3-MKK7-JNK3 signaling pathway[J]. Cell Physiol Biochem, 2016, 39(4): 1433-1443.
[DOI]
|
| [57] |
He P, Zhang D, Li H, Yang X, Li D, Zhai Y, Ma L, Feng G. Hepatitis B virus X protein modulates apoptosis in human renal proximal tubular epithelial cells by activating the JAK2/STAT3 signaling pathway[J]. Int J Mol Med, 2013, 31(5): 1017-1029.
[DOI]
|
| [58] |
Hong L, Zhang J, Min J, Lu J, Li F, Li H, Guo S, Li Q. A role for MHBst167/HBx in hepatitis B virus-induced renal tubular cell apoptosis[J]. Nephrol Dial Transplant, 2010, 25(7): 2125-2133.
[DOI]
|
| [59] |
Wang X, Zhou Y, Zhu N, Wang L, Gu LJ, Yuan WJ. The deposition of Notch1 in hepatitis B virus-associated nephropathy and its role in hepatitis B virus X protein-induced epithelial-mesenchymal transdifferentiation and immunity disorder in renal tubular epithelial cells[J]. J Viral Hepat, 2014, 21(10): 734-743.
[DOI]
|
| [60] |
Wang Y, Liu C, Hong S, Zhang P, Liu Q. Effect of recombinant Hepatitis B virus on human glomerular mesangial cell apoptosis[J]. Biotechnol Biotechnol Equip, 2014, 28(4): 689-696.
[DOI]
|
| [61] |
Hui D, Yan X, Wei J, Ruixia M, Guangju G. Significance of mutations in hepatitis B virus X gene for the pathogenesis of HB-associated glomerulonephritis[J]. Acta Virol, 2014, 58(3): 278-281.
[DOI]
|
| [62] |
Li D, Gao G, Jiang H, Tang Z, Yu Y, Zang G. Hepatitis B virus-associated glomerulonephritis in HBsAg serological-negative patients[J]. Eur J Gastroenterol Hepatol, 2015, 27(1): 65-69.
[DOI]
|
| [63] |
Wang W, Sun L, Li T, Ma Y, Li J, Liu Y, Li M, Wang L, Li C, Xie Y, Wen Y, Liang M, Chen L, Tong S. A human monoclonal antibody against small envelope protein of hepatitis B virus with potent neutralization effect[J]. MAbs, 2016, 8(3): 468-477.
[DOI]
|
| [64] |
Zhang TY, Yuan Q, Zhao JH, Zhang YL, Yuan LZ, Lan Y, Lo YC, Sun CP, Wu CR, Zhang JF, Zhang Y, Cao JL, Guo XR, Liu X, Mo XB, Luo WX, Cheng T, Chen YX, Tao MH, Shih JW, Zhao QJ, Zhang J, Chen PJ, Yuan YA, Xia NS. Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis B surface antigen[J]. Gut, 2016, 65(4): 658-671.
[DOI]
|
| [65] |
Li C, Wang Y, Liu T, Niklasch M, Qiao K, Durand S, Chen L, Liang M, Baumert TF, Tong S, Nassal M, Wen YM, Wang YX. An E. coli-produced single-chain variable fragment (scFv) targeting hepatitis B virus surface protein potently inhibited virion secretion[J]. Antiviral Res, 2019, 162: 118-129.
[DOI]
|
| [66] |
Kruse RL, Shum T, Tashiro H, Barzi M, Yi Z, Whitten-Bauer C, Legras X, Bissig-Choisat B, Garaigorta U, Gottschalk S, Bissig KD. HBsAg-redirected T cells exhibit antiviral activity in HBV-infected human liver chimeric mice[J]. Cytotherapy, 2018, 20(5): 697-705.
[DOI]
|
| [67] |
Krebs K, Böttinger N, Huang LR, Chmielewski M, Arzberger S, Gasteiger G, Jäger C, Schmitt E, Bohne F, Aichler M, Uckert W, Abken H, Heikenwalder M, Knolle P, Protzer U. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice[J]. Gastroenterology, 2013, 145(2): 456-465.
[DOI]
|
| [68] |
Jiang M, Broering R, Trippler M, Poggenpohl L, Fiedler M, Gerken G, Lu M, Schlaak JF. Toll-like receptor-mediated immune responses are attenuated in the presence of high levels of hepatitis B virus surface antigen[J]. J Viral Hepat, 2014, 21(12): 860-872.
[DOI]
|
| [69] |
Op den Brouw ML, Binda RS, van Roosmalen MH, Protzer U, Janssen HL, van RG, Woltman AM. Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus[J]. Immunology, 2009, 126(2): 280-289.
[DOI]
|
| [70] |
Shi B, Ren G, Hu Y, Wang S, Zhang Z, Yuan Z. HBsAg inhibits IFN-alpha production in plasmacytoid dendritic cells through TNF-alpha and IL-10 induction in monocytes[J]. PLoS One, 2012, 7(9): e44900.
[DOI]
|
| [71] |
Wang S, Chen Z, Hu C, Qian F, Cheng Y, Wu M, Shi B, Chen J, Hu Y, Yuan Z. Hepatitis B virus surface antigen selectively inhibits TLR2 ligand-induced IL-12 production in monocytes/macrophages by interfering with JNK activation[J]. J Immunol, 2013, 190(10): 5142-5151.
[DOI]
|
| [72] |
Wu J, Meng Z, Jiang M, Pei R, Trippler M, Broering R, Bucchi A, Sowa JP, Dittmer U, Yang D, Roggendorf M, Gerken G, Lu M, Schlaak JF. Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells[J]. Hepatology, 2009, 49(4): 1132-1140.
[DOI]
|
| [73] |
Xu Y, Hu Y, Shi B, Zhang X, Wang J, Zhang Z, Shen F, Zhang Q, Sun S, Yuan Z. HBsAg inhibits TLR9-mediated activation and IFN-alpha production in plasmacytoid dendritic cells[J]. Mol Immunol, 2009, 46(13): 2640-2646.
[DOI]
|
| [74] |
Feng S, Gao L, Han X, Hu T, Hu Y, Liu H, Thomas AW, Yan Z, Yang S, Young JAT, Yun H, Zhu W, Shen HC. Discovery of small molecule therapeutics for treatment of chronic HBV infection[J]. ACS Infect Dis, 2018, 4(3): 257-277.
[DOI]
|