HK-2腎乳頭狀瘤細胞

HK-2（Human Kidney-2）是具有良好分化能力的人類腎乳頭狀瘤細胞系，最初分離自一位成年男性腎乳頭狀瘤患者的腎近曲小管（proximal convoluted tubule）細胞，通過導入人類乳頭瘤病毒-16 E6/E7基因而成為永生化的腎乳頭狀瘤細胞系[1]。自1984年首次分離及培養以來，受到許多科研人員的關注[2]。

特徵

HK-2細胞已知會對表皮生長因子、鹼性磷酸酶、γ-谷氨醯轉肽酶、白胺酸胺肽酶（英语：Leucyl aminopeptidase）、酸性磷酸酶、細胞角蛋白（英语：Cytokeratin）、αVβ3整聯蛋白及纖連蛋白呈陽性反應，並且對6.19抗原和CALLA內肽酶（CALLA endopeptidase）呈陰性反應[1]。HK-2細胞保留了腎近曲小管的功能性特徵，例如鈉依賴性和對根皮苷（英语：Phlorizin）敏感的糖轉運，以及腺苷酸環化酶對甲狀旁腺的反應，但是對抗利尿激素的反應性不高[1]。HK-2細胞因具有產生和儲存糖原的能力而被指具有糖質新生的能力。此外，因為HK-2細胞是錨定依賴性的，所以不會在甲基纖維素、軟瓊脂或懸浮液中生長。

HK-2細胞主要通過頂端表面合成和分泌血漿蛋白。有研究證明即使在靜止狀態下，HK-2細胞在補體C3的複合物中表達mRNA，並且合成和分泌着血漿蛋白，而約90％的血漿蛋白分泌到頂端，而小部分則分泌到基底外側。當在腫瘤壞死因子-α等外源性細胞因子存在的情況下進行培養時，HK-2細胞血漿蛋白mRNA表達會受到不同程度的影響，而在基底外側的分泌升高至頂端水平，又或者超過頂端水平。除此之外，HK-2細胞保持了從培養基中快速攝取外源添加性血清蛋白的能力[3]。

研究用途

細胞毒性

目前廣泛應用於科研用途，並且是研究腎毒性的常用細胞模型。Murphy等作出的研究表明HK-2細胞是對替諾福韋（TFV）細胞毒性敏感的模型，並且表明經TFV處理的HK-2細胞發生線粒體應激和細胞凋亡[4]。此外，Lin等作出的研究發現黃芩苷通過抑制內質網應激和激活Nrf2信號傳導，以減輕過氧化氫誘導的HK-2細胞細胞毒性[5]。

Gunness等在研究藥物誘導的腎毒性方面比較了HK-2細胞與LLC-PK1細胞。他們檢查了兩種腎毒性藥物，即異環磷醯胺和阿昔洛韋對HK-2細胞的影響，結果發現HK-2細胞將異環磷醯胺代謝為氯乙醛。阿昔洛韋則濃度依賴性降低HK-2的細胞活性，這表明阿昔洛韋可能誘導對腎近曲腎小管細胞的直接損傷。這些結果表明HK-2細胞是用於體外毒性研究，以及確定藥物誘導的人類腎毒性的合適模型[6]。

實驗模型

Jenkinson等作出的研究發現HK-2細胞作為藥物轉運蛋白表達和近曲小管功能模型的局限性，並表示HK-2細胞在該方面的價值有限[7]。Gildea等作出的研究發現HK-2細胞可以作為GRK4介導多巴胺-1受體解偶聯的模型。因為他們發現HK-2細胞會在多巴胺-1受體（D1R）腺苷酸環化酶（AC）的刺激下解偶聯，並且假設了G蛋白偶聯受體激酶4型（GRK4）單核苷酸多態性可能是HK-2細胞中D1R/AC解偶聯的原因。除此之外，他們還發現HK-2細胞保留腎近曲小管細胞的許多功能性特徵，但是從多巴胺能功能的角度來看，它不是正常的[8]。

增殖及凋亡

Lu等作出的研究發現小檗鹼通過抑制SPHK1的表達，保護HK-2細胞免受缺氧或復氧所誘導的凋亡，並且發現小檗鹼會下調p-P38、胱天蛋白酶-3、胱天蛋白酶-9的表達，以及向上調節Bcl-2（英语：Bcl-2）/Bax（英语：Bcl-2-associated X protein）的比例。SPHK1在HK-2細胞中的過度表達會誘導嚴重的細胞凋亡，如果對細胞進行小檗鹼處理，則可以顯著改善細胞凋亡[9]。除此之外，Huang等作出的研究發現GLIPR-2在HK-2細胞中的過度表達，通過ERK1/2的激活，促進細胞上皮-間質轉化和遷移能力[10]。

參考資料

  1. ^ 1.0 1.1 1.2 Ryan, MJ; Johnson, G; Kirk, J; Fuerstenberg, SM; Zager, RA; Torok-Storb, B. HK-2: an immortalized proximal tubule epithelial cell line from normal adult human kidney.. Kidney international. 1994-01, 45 (1): 48–57 [2020-02-18]. PMID 8127021. doi:10.1038/ki.1994.6. （原始内容存档于2020-02-18）. 
  2. ^ Detrisac, CJ; Sens, MA; Garvin, AJ; Spicer, SS; Sens, DA. Tissue culture of human kidney epithelial cells of proximal tubule origin.. Kidney international. 1984-02, 25 (2): 383–90 [2020-02-18]. PMID 6727133. doi:10.1038/ki.1984.28. （原始内容存档于2020-02-18）. 
  3. ^ Zhao, KW; Murray, EJ; Murray, SS. HK2 Proximal Tubule Epithelial Cells Synthesize and Secrete Plasma Proteins Predominantly Through the Apical Surface.. Journal of cellular biochemistry. 2017-04, 118 (4): 924–933 [2020-02-18]. PMID 27862254. doi:10.1002/jcb.25786. （原始内容存档于2020-02-18）. 
  4. ^ Murphy, RA; Stafford, RM; Petrasovits, BA; Boone, MA; Valentovic, MA. Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity.. International journal of molecular sciences. 2017-03-01, 18 (3) [2020-02-18]. PMID 28257038. doi:10.3390/ijms18030531. （原始内容存档于2020-02-18）. 
  5. ^ Lin, M; Li, L; Zhang, Y; Zheng, L; Xu, M; Rong, R; Zhu, T. Baicalin ameliorates H2O2 induced cytotoxicity in HK-2 cells through the inhibition of ER stress and the activation of Nrf2 signaling.. International journal of molecular sciences. 2014-07-15, 15 (7): 12507–22 [2020-02-18]. PMID 25029541. doi:10.3390/ijms150712507. （原始内容存档于2020-02-18）. 
  6. ^ Gunness, P; Aleksa, K; Kosuge, K; Ito, S; Koren, G. Comparison of the novel HK-2 human renal proximal tubular cell line with the standard LLC-PK1 cell line in studying drug-induced nephrotoxicity.. Canadian journal of physiology and pharmacology. 2010-04, 88 (4): 448–55 [2020-02-18]. PMID 20555413. doi:10.1139/y10-023. （原始内容存档于2020-02-18）. 
  7. ^ Jenkinson, SE; Chung, GW; van Loon, E; Bakar, NS; Dalzell, AM; Brown, CD. The limitations of renal epithelial cell line HK-2 as a model of drug transporter expression and function in the proximal tubule.. Pflugers Archiv : European journal of physiology. 2012-12, 464 (6): 601–11 [2020-02-18]. PMID 23014881. doi:10.1007/s00424-012-1163-2. （原始内容存档于2020-02-18）. 
  8. ^ Gildea, JJ; Shah, I; Weiss, R; Casscells, ND; McGrath, HE; Zhang, J; Jones, JE; Felder, RA. HK-2 human renal proximal tubule cells as a model for G protein-coupled receptor kinase type 4-mediated dopamine 1 receptor uncoupling.. Hypertension (Dallas, Tex. : 1979). 2010-09, 56 (3): 505–11 [2020-02-18]. PMID 20660820. doi:10.1161/HYPERTENSIONAHA.110.152256. （原始内容存档于2020-02-18）. 
  9. ^ Lu, J; Yi, Y; Pan, R; Zhang, C; Han, H; Chen, J; Liu, W. Berberine protects HK-2 cells from hypoxia/reoxygenation induced apoptosis via inhibiting SPHK1 expression.. Journal of natural medicines. 2018-03, 72 (2): 390–398 [2020-02-18]. PMID 29260413. doi:10.1007/s11418-017-1152-z. （原始内容存档于2020-02-18）. 
  10. ^ Huang, S; Liu, F; Niu, Q; Li, Y; Liu, C; Zhang, L; Ni, D; Pu, X. GLIPR-2 overexpression in HK-2 cells promotes cell EMT and migration through ERK1/2 activation.. PloS one. 2013, 8 (3): e58574 [2020-02-18]. PMID 23516513. doi:10.1371/journal.pone.0058574. （原始内容存档于2020-02-18）. 

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