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Effects of GABA on Erythropoiesis in the Hep3B Cell and Rat Exposed to Hypoxia
Biomed Sci Letters 2021;27:69-76
Published online June 30, 2021;  https://doi.org/10.15616/BSL.2021.27.2.69
© 2021 The Korean Society For Biomedical Laboratory Sciences.

Joongsoo Yoon* and In-Suk Sim†,*

Department of Clinical Laboratory Science, Kyungdong University, Wonju 26495, Korea
Correspondence to: In-Suk Sim. Department of Clinical Laboratory Science, Kyungdong University, Wonju 26495, Korea.
Tel: +82-33-738-1374, Fax: +82-33-738-1379, e-mail: simis@kduniv.ac.kr
*Professor.
Received April 15, 2021; Revised June 1, 2021; Accepted June 4, 2021.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
The aim of this study was to evaluate gamma-aminobutyric acid (GABA)-induced erythropoietin (EPO) and EPOreceptor expression in human Hep3B cells and Sprague Dawley (SD) rats during hypoxia. Expression levels of EPO, EPO-R mRNA, Janus kinase-2 (JAK-2), vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1), and HIF-2 in response to GABA treatment were evaluated in cell lines. SD rats were randomly divided into 5 groups of 8 rats each, and GABA was orally administered; the groups were the normal control (NC), hypoxia-exposed (G0), as well as the GABA 1 mg/100 g body weight (BW) GABA treated group (G1), 5 mg/100 g BW GABA treated group (G5), and 10 mg/100 g BW GABA treated group (G10) with hypoxia. We analyzed EPO levels and red blood cell counts in rat blood and EPO gene expression in kidney tissue. EPO and VEGF mRNA levels in Hep3B cells exposed to hypoxia were significantly increased and further increased after GABA treatment. However, the expression of EPO-R and JAK-2 mRNAs were not affected by GABA, but hypoxia-induced HIF-1 and HIF-2 mRNA expression was inhibited by GABA. In the kidney tissue of rats exposed to hypoxia, the expression level of EPO mRNA was greatly increased, but levels in the GABA treatment groups significantly decreased. EPO levels in the serum showed the same significant trend, but the red blood cell counts were not significantly different. These findings demonstrate that HIF-1 and HIF-2 activation increase EPO expression in Hep3B cells exposed to hypoxia. However HIF decreased by GABA addition and VEGF increased significantly.
Keywords : GABA, Hypoxia, Hep3B cell, Erythropoiesis, Rat
꽌 濡

씤泥대뒗 궛냼냽룄 蹂솕뿉 誘쇨컧븯寃 諛섏쓳븯뿬, 씠뿉 쟻쓳븯뒗 꽭룷 諛 媛쒖껜쓽 솢룞 깮議댁뿉 븘닔쟻씠硫, 빆긽꽦 쑀吏뿉룄 留ㅼ슦 以묒슂븯떎(Semenza, 2000). 듅엳, 怨좎 媛숈 궛냼 긽깭(hypoxia)뿉꽌뒗 떊泥댁쓽 쟻쓳 諛섏쓳쓣 옄洹뱀떆궎湲 쐞빐 궛냼슫諛섏쓣 利앷떆궎硫, 씠뿉 愿뿬븯뒗 떒諛깆쭏씠 겕寃 諛쒗쁽릺뼱 궛냼 긽깭뿉 쟻쓳븳떎(Mazzeo, 2005). 궛냼뿉 2~3씪媛 끂異쒕릺硫 쟻삁援 議고삁씤옄(erythropoietin, EPO)쓽 遺꾨퉬媛 利앷릺怨, 3二 씠썑뿉뒗 쟻삁援, hemoglobin, hematocrit씠 利앷맂떎(Levine and Stray-Gundersen, 1992; Chapman et al., 1998). 肉먮쭔 븘땲씪, 샇씉 利앷, 삁愿 솗옣, 삁愿 떊깮쓽 利앷, gluconeogenesis쓽 媛먯냼, ATP 깮꽦 諛섏쓳 媛먯냼 벑쓽 쁽긽씠 굹굹硫, 씠 以 삁愿 떊깮씠 媛옣 옣湲곗쟻씠怨 슚怨쇱쟻씤 쟻쓳 諛섏쓳씠떎.

Gamma-aminobutyric acid (GABA)뒗 以묒텛떊寃쎄퀎뿉꽌 뼲젣꽦 떊寃쎌쟾떖 臾쇱쭏씠硫, 留먯큹 鍮꾩떊寃쎄퀎 議곗쭅뿉꽌 以묒슂븳 깮由ъ쟻 뿭븷쓣 븳떎(Minuk, 1993: Takano et al., 2014). GABAergic 쉶濡쒖쓽 蹂寃쎌 뙆궓뒯蹂 諛 끂씤꽦 移섎ℓ 媛숈 떊寃쏀븰쟻 옣븷 愿젴씠 엳떎(Ting Wong et al., 2003). GABA뒗 떊옣쓣 룷븿븳 留먯큹 議곗쭅뿉 議댁옱븯硫, 留뚯꽦 떊옣吏덊솚쓣 삁諛⑺븯怨, 떊옣젅젣닠뿉 쓽빐 쑀諛쒕맂 궛솕 뒪듃젅뒪瑜 媛쒖꽑븯怨, 媛꾧낵 떊옣湲곕뒫뿉 쁺뼢쓣 以 닔 엳떎(Sasaki et al., 2006). 떎瑜 뿰援щ뒗 GABA媛 쑀꽑, 寃곗옣 諛 媛꾩븫꽭룷 媛숈 떎뼇븳 쑀삎쓽 븫꽭룷쓽 移⑥쑄怨 쟾씠瑜 吏뿰떆궎嫄곕굹 뼲젣븷 닔 엳떎怨 젣븞븯쑝硫, 빆뿼利 諛 꽟쑀 븘꽭룷 利앹떇쓣 珥됱쭊븯뿬 뵾遺 긽泥섏쓽 移섏쑀뿉 룄쓣 以떎怨 蹂닿퀬릺뿀떎(Kleinrok et al., 1998; Minuk, 2000; Opolski et al., 2000; Han et al., 2007).

Erythropoietin (EPO) 떊옣뿉꽌 깮꽦맂 궗씠넗移댁씤쑝濡 怨⑥닔뿉꽌쓽 쟻삁援 깮꽦쓣 議곗젅븳떎(Salahudeen et al., 2008). 꽦씤뿉꽌 EPO뒗 떊옣 뵾吏덉쓽 꽟쑀 紐⑥꽭룷뿉 쓽빐 깮꽦릺硫, hypoxia inducible factor (HIF)濡 씤빐 EPO 쑀쟾옄쓽 쟾궗瑜 議곗젅븳떎(Haase, 2006; Jelkmann, 2013). EPO 깮꽦 Janus kinase 떊샇쟾떖 寃쎈줈쓽 솢꽦솕 諛 protein kinase B쓽 씤궛솕 諛 apoptosis쓽 뼲젣瑜 넻빐 EPO receptor 蹂듯빀泥댁뿉 寃고빀븿쑝濡쒖뜥 떊옣 蹂댄샇 슚怨쇰 굹궦떎(Buemi et al., 2003; Chatterjee, 2007).

理쒓렐뿉 蹂닿퀬맂 臾명뿄뿉 쓽븯硫, GABA쓽 꽠痍⑤줈 씤빐 뤌吏쓽 떊옣 긽뵾꽭룷二쇱뿉꽌 EPO EPO receptor쓽 諛쒗쁽씠 利앷맂 蹂닿퀬媛 엳뒗 諛(Lee et al., 2018; Shin et al., 2019), 蹂 뿰援ъ뿉꽌뒗 Hep3B cell怨 씛伊먯뿉寃 GABA瑜 닾뿬 썑 궛냼 솚寃쎌뿉 끂異쒖떆궎怨 EPO 諛 洹몄 愿젴맂 쑀쟾옄 諛쒗쁽쓣 遺꾩꽍 諛 삁븸 궡 떎젣 EPO 닔移섎 遺꾩꽍븯떎. 궛냼 솚寃쎌뿉꽌 GABA濡 씤븳 EPO 깮꽦怨쇱젙쓽 湲곗쟾 蹂솕瑜 遺꾩꽍븯쑝硫, in vitro in vivo뿉꽌쓽 諛쒗쁽뼇긽쓽 李⑥씠瑜 솗씤븯떎.

옱猷 諛 諛⑸쾿

꽭룷 諛곗뼇

蹂 떎뿕뿉꽌 궗슜븳 Human hepatoma cell line, Hep3B cell 븳援꽭룷二쇱뻾(Seoul, Korea)뿉꽌 遺꾩뼇 諛쏆븯떎. 100 mm culture dish뿉꽌 10% fetal bovine serum, 1% penicillin /streptomycin쓣 븿쑀븳 Dulbeccós Modified Eaglés Medium (DMEM)쓣 궗슜븯뿬 37꼦, 5% CO2 議곌굔뿉꽌 諛곗뼇븯떎. 96-well plate쓽 媛 well留덈떎 1 × 104媛쒖쓽 꽭룷瑜 seeding븳 썑 24떆媛 룞븞 諛곗뼇떆耳곕떎. 洹 썑 삁泥씠 룷븿릺吏 븡 諛곗濡 援먰솚븳 썑 議곌렇猷뱀뿉뒗 distilled water, 떎뿕洹몃9뿉뒗 媛곴컖 1 μM, 10 μM, 50 μM, 100 μM, 250 μM, 500 μM, 1,000 μM쓽 GABA瑜 泥섎━븯떎. 떎떆 24떆媛 룞븞 諛곗뼇떆궓 썑 諛곗瑜 젣嫄고븯怨 0.5 mg/mL쓽 MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)瑜 100 μL 泥④븯뿬 formazan쓣 삎꽦븳 썑 DMSO (Dimethyl sulfoxide) 50 μL瑜 泥④븯뿬 Versamax microplate reader (Molecular devices, Sunnyvale, CA, USA)瑜 궗슜븯뿬 씉愿묐룄(540 nm)瑜 痢≪젙븯떎. EPO 愿젴 쑀쟾옄 諛쒗쁽遺꾩꽍쓣 쐞븳 꽭룷諛곗뼇 議곌굔 MTT 떎뿕 議곌굔怨 룞씪븯寃 吏꾪뻾븯쑝硫, GABA쓽 泥④닔以쓣 50 μM, 100 μM, 500 μM 닔以쑝濡 議곗젙븯떎.

꽭룷 궛냼 솚寃 議곗꽦

궛냼利앹 떎뼇븳 꽭룷쓽 꽦옣뿉 쁺뼢쓣 二쇰ʼn 솢꽦궛냼醫낆쓣 깮꽦떆耳 apoptosis瑜 빞湲고븳떎. 뵲씪꽌 궛냼利앹쓣 쑀룄븷 닔 엳뒗 CoCl2瑜 씠슜븯뿬 꽭룷떎뿕쓣 닔뻾븯떎. Hep3B 꽭룷瑜 怨꾨諛곗뼇븯怨 GABA瑜 뿬윭 냽룄濡 5씪媛 泥섎━븯쑝硫, 12떆媛 썑뿉 CoCl2瑜 50 μM쓽 냽룄濡 泥④븯떎. CoCl2 泥섎━ 4떆媛 썑 꽭룷瑜 紐⑥븘 遺꾩꽍뿉 궗슜븯떎.

떎뿕룞臾

떎뿕룞臾쇱 5二쇰졊쓽 닔而 Sprague-dawley rat쓣 (二)肄붿븘뀓(룊깮, 븳援)뿉꽌 援ъ엯븯뿬 1二쇱씪媛 궗쑁옣 솚寃쎌뿉 쟻쓳떆궓 썑 洹몃9떦 8留덈━뵫 臾댁옉쐞濡 굹늻뼱 궗슜븯떎. GABA瑜 3二쇨컙 1 mg/100 g BW, 5 mg/100 g BW, 10 mg/100 g BW쓽 냽룄濡 寃쎄뎄닾뿬 뻽쑝硫, 씠썑 5씪 룞븞뿉룄 GABA瑜 꽠痍 諛 븯猷 1떆媛꾩뵫 궛냼 솚寃쎌뿉 끂異쒖떆耳곕떎. 臾쇨낵 궗猷뚮뒗 옄쑀濡寃 꽠痍⑦븯룄濡 븯怨 궗슜븳 궗猷뚮뒗 꽕移섎쪟 궗猷(LabDiet 5001 Rodent Diet, Purina, Table 1)瑜 궗슜븯떎. 궗쑁옣쓽 떎궡삩룄뒗 22±4꼦, 뒿룄 60±10%, 議곕룄뒗 200~300 Lux濡 쑀吏븯쑝硫, 12떆媛 紐낆븫二쇨린媛 릺룄濡 議곗젅븯떎. 룞臾쇱떎뿕 怨좊젮븰援 룞臾쇱쑄由ъ쐞썝쉶쓽 듅씤(Approval No. KUIACUC-2017-95)쓣 뼸뼱 닔뻾븯떎. 떎뿕씠 醫낅즺맂 썑 媛 룞臾쇱쓽 떊옣遺遺꾩쓣 쟻異쒗븯뿬 EPO 諛 씠 愿젴맂 쑀쟾옄 諛쒗쁽遺꾩꽍뿉 궗슜븯떎. 삁븸 븞씫궗 썑 紐⑤뱺 룞臾쇱뿉꽌 梨꾪삁븯쑝硫, 삁援щ텇꽍 EDTA媛 泥④맂 吏꾧났 삁븸 뒠釉뚯뿉 꽔뼱 遺꾩꽍 떆源뚯 4꼦뿉 蹂닿븯怨, 4떆媛 궡뿉 rat 쟾슜 삁援щ텇꽍옣鍮꾨 궗슜븯뿬 遺꾩꽍븯떎. 삁泥遺꾩꽍 빆쓳怨좎젣媛 뾾뒗 吏꾧났뒠釉뚮 궗슜븯怨, 3,000 rpm뿉꽌 10遺꾧컙 썝떖遺꾨━븯뿬 긽痢 삁泥쓣 EPO 遺꾩꽍뿉 궗슜븯떎.

Composition of experimental diets

Ingredients %
Protein 23.0
Carbohydrate 49.5
Fiber 6.0
Fat 4.5
Others* 17.0
Calories (kcal/g) 3.5

Normal laboratory diet (Purina LabDiet 5001)

*Others: vitamins, minerals, and water



룞臾 궛냼 솚寃 議곗꽦

궛냼 솚寃쎌 쇅遺 怨듦린 李⑤떒맂 hypoxia chamber (COY, O2 Control In Vivo Cabinet, USA)瑜 궗슜븯떎. Hypoxia pump瑜 씠슜븯뿬 chamber 궡濡 궛냼냽룄 9%, 吏덉냼 92%媛 릺룄濡 議곗꽦븯쑝硫, 븯猷 30遺 룞븞 끂異쒖떆耳곕떎.

삁泥 諛 꽭룷 궡 EPO 遺꾩꽍

삁泥 諛 꽭룷쓽 EPO 遺꾩꽍 ELISA kit (Cat# CSB-07323r, CUSABIO CO., LTD, China)瑜 궗슜븯떎.

Reverse transcription-polymerase chain reaction

떎뿕씠 醫낅즺맂 룞臾쇱쓽 떊옣 遺쐞瑜 쟻異쒗븯怨, 議곗쭅 떦 룞씪遺遺꾩뿉꽌 RNeasy min kit (QIAGEN)쓣 궗슜븯뿬 留ㅻ돱뼹뿉 뵲씪 RNA瑜 遺꾨━븯떎. 遺꾨━맂 RNA뒗 1st strand cDNA kit (Roche)瑜 궗슜븯뿬 cDNA瑜 빀꽦븯떎. 10X buffer 2.0 μL, 25 mM MgCl 4.0 μL, dNTP 2.0 μL, oligo-dT primer 2.0 μL, RNasin 1.0 μL, AMV reverse transcriptase 0.8 μL쓽 mixture뿉 RNA 500 μL쓣 泥④븯뿬 sterile water濡 20.0 μL媛 릺寃 븳 썑, Thermo cycler (9700, Applied biosystem)뿉꽌 25꼦뿉꽌 10遺, 42꼦뿉꽌 60遺, 95꼦뿉꽌 5遺꾧컙 諛섏쓳떆耳 cDNA瑜 빀꽦븯떎. 빀꽦맂 cDNA뒗 2X probe mixture (Roche)瑜 궗슜븯뿬 LC480 realtime PCR 옣鍮 (Roche)뿉꽌 諛쒗쁽웾쓣 遺꾩꽍븯떎. 2X LC480 probe master mix (Roche) 10 μL, 20 pM forward 諛 reverse primer 1.0 μL, 20 pM probe 0.2 μL쓽 mixture뿉 cDNA 1.0 μL瑜 泥④븯뿬 sterile water濡 20 μL媛 릺寃 븳 썑, LC480 realtime PCR 옣鍮(Roche)濡 95꼦뿉꽌 3遺꾧컙 predenaturation, 95꼦뿉꽌 10珥, 60꼦뿉꽌 30珥덈 40쉶 諛섎났븯뿬 諛쒗쁽웾쓣 2-ΔΔCt 踰뺤쑝濡 遺꾩꽍븯떎. 紐⑤뱺 떎뿕 2쉶 諛섎났븯쑝硫, PCR뿉 궗슜맂 쑀쟾옄쓽 씠由 諛 뿼湲곗꽌뿴 Table 2 媛숇떎.

Primer sequences

Gene symbol Sense (5'-3') Antisense (5'-3')
EPO TACGTAGCCTCACTTCACTGCTT GCAGAAAGTAT CG TGTGAG TGT TC
EPOR AGGTGGACGTGTCAGCAGGC CGTACCTTGTGGCGTATGCAG
HIF-1a CACTGCACAGGCCACATTCAT AAGCAGGTCATAGGCGGTTTC
HIF-2a GTCACCAGAACTTGTGC CAAAGATGCTGTT
JAK-2 GGCAGCAGCAGAACCTAC GTCTAACACCGCCATCCC
VEGF AACGAAAGCGCAAGAAATCC GCTCACAGTGAACGCTCCAG
Actin CTTTCTACAATGAGCTGCGTG TCATGAGGTAGTCTGTCAGG

EPO, erythropoietin; EPOR, erythropoietin receptor; HIF, hypoxia inducible factor; JAK-2, janus kinase 2; VEGF, Vascular endothelial growth factor



넻怨꾩쿂由

넻怨꾨텇꽍 SPSS program (SPSS Inc., Chicago, USA)쓣 씠슜븯뿬 룊洹좉낵 몴以렪李(mean ± SD)濡 젣떆븯쑝硫, 媛 洹몃9쓽 쑀쓽꽦 遺꾩꽍 떆뿕洹몃9쓽 痢≪젙移섏뿉 빐 Student t-test 寃젙쓣 쟻슜븯뿬 P < 0.05 씠븯쓽 쑀쓽닔以뿉꽌 쑀쓽꽦 寃젙쓣 떎떆븯떎. 泥섎━援ш컙쓽 쑀쓽꽦 Duncan's multiple range-test瑜 씠슜븯뿬 5% 닔以뿉꽌 寃젙븯떎.

寃곌낵 諛 怨좎같

꽭룷 룆꽦

Hep3B cell쓣 諛곗뼇떆궓 썑 GABA (1 μM, 10 μM, 50 μM, 100 μM, 250 μM, 500 μM)瑜 24떆媛 룞븞 泥섎━븯뿬 MTT濡 Cell viability瑜 痢≪젙븳 寃곌낵, 議곌렇猷뱀뿉 鍮꾪빐 媛곴컖 98.90%, 98.07%, 99.67%, 103.43%, 103.38%, 100.24%, 102.34%濡 굹궗쑝硫 GABA媛 Hep3B cell뿉 룆꽦쓣 굹궡吏 븡뒗떎뒗 寃껋쓣 솗씤븯떎(Fig. 1).

Fig. 1. MTT Assay in co-culture of Hep3B cells after an overnight incubation with 1, 10, 100 and 500 μg GABA / mL. The absorbance of the MTT formazan was determined at 570 nm in an ELISA reader. Cell viability was defined as the ratio (expressed as a percentage) of absorbance of treated cells to untreated cells. Values given represent the mean ± standard deviations of three independent experiments carried out in triplicates.

꽭룷 궡 EPO 諛 愿젴 쑀쟾옄 諛쒗쁽

Hep3B cell쓣 CoCl2뿉 끂異쒖떆궓 썑 꽭룷 궡 EPO 愿젴 쑀쟾옄뱾쓽 諛쒗쁽쓣 遺꾩꽍븯떎(Fig. 2). 꽭룷 궡 EPO쓽 諛쒗쁽 議곌렇猷뱀뿉 鍮꾪빐 G0 洹몃9뿉꽌 빟 8.7諛 利앷븯쑝硫, GABA 泥④洹몃9씤 G50, G100, G200 洹몃9뿉꽌뒗 G0 洹몃9뿉 鍮꾪빐 媛곴컖 55.7±3.77%, 39.3±2.80%, 37.1±2.14%濡 쑀쓽븯寃 利앷븯떎. EPO receptor쓽 諛쒗쁽遺꾩꽍 寃곌낵 NC 洹몃9뿉 鍮꾪빐 紐⑤뱺 洹몃9뿉꽌 빟 34.3±1.1%쓽 닔以쑝濡 쑀쓽븯寃 媛먯냼븯떎. Janus kinase 2 (JAK2)쓽 諛쒗쁽遺꾩꽍 寃곌낵뿉꽌룄 NC 洹몃9뿉 鍮꾪빐 紐⑤뱺 洹몃9뿉꽌 빟 37.2±7.25% 닔以쑝濡 쑀쓽븯寃 媛먯냼븯떎. 諛섎㈃ VEGF쓽 諛쒗쁽遺꾩꽍 寃곌낵, NC 洹몃9뿉 鍮꾪빐 G0 洹몃9뿉꽌 빟 53.1±6.54%媛 利앷븯쑝硫, G50, G100, G500 泥④洹몃9뿉꽌뒗 G0 洹몃9뿉 鍮꾪빐 媛곴컖 23.5±9.58%, 28.8±8.12%, 26.8±5.14% 利앷븯쑝굹 쑀쓽쟻씠吏뒗 븡븯떎. HIF-1쓽 諛쒗쁽遺꾩꽍 寃곌낵 NC 洹몃9뿉 鍮꾪빐 G0 洹몃9뿉꽌 60±1.88% 利앷븯쑝硫, G500 洹몃9뿉꽌 쑀씪븯寃 G0 洹몃9뿉 鍮꾪빐 8.1±2.94% 쑀쓽븯寃 媛먯냼븯떎. HIF-2쓽 諛쒗쁽遺꾩꽍 寃곌낵 HIF-1怨 쑀궗븳 寃곌낵媛 솗씤릺뿀떎. NC 洹몃9뿉 鍮꾪빐 G0 洹몃9뿉꽌 73±2.32% 利앷븯쑝굹, G500 洹몃9뿉꽌 G0 洹몃9뿉 鍮꾪빐 쑀씪븯寃 26.0±1.56% 媛먯냼븯떎.

Fig. 2. Effect of different concentrations of GABA on EPO and its related gene expression in Hep3B cell exposed to hypoxia. Gene expression of (A) EPO, (B) EPO receptor, (C) JAK-2, (D) VEGF, (E) HIF-1, (F) HIF-2. Data represent ration in mean ± SEM of experiment. Different letters indicate significant difference of the means (P<0.05). EPO, erythropoietin; JAK-2, janus kinase 2; HIF-1, hypoxia inducible factor 1; HIF-2, hypoxia inducible factor 2; VEGF, vascular endothelial growth factor.

EPO뒗 떊옣怨 媛꾩뿉꽌 깮꽦릺硫, 궛냼 긽깭濡 엳쑝硫 EPO쓽 깮궛씠 빆吏꾨릺뼱 삁옣 EPO媛 利앷븯硫, 씠寃껋씠 怨⑥닔쓽 媛꾩꽭룷뿉 옉슜븯뿬 쟻삁援щ줈쓽 遺꾪솕瑜 쑀룄븳떎(Silver and Erslev, 1974; Jelkmann, 2007). 蹂 떎뿕뿉꽌룄 5씪媛 1떆媛꾩뵫 궛냼 솚寃쎌쓣 議곗꽦븳 CoCl2 泥섎━ 洹몃9뿉꽌룄 EPO쓽 諛쒗쁽웾씠 빟 8諛 씠긽 利앷븯떎. GABA瑜 泥섎━븳 洹몃9뿉꽌룄 EPO쓽 諛쒗쁽웾씠 쑀쓽븯寃 利앷븯쑝硫, 꽭룷 궡뿉꽌 GABA媛 EPO瑜 利앷떆궓떎뒗 蹂닿퀬 씪移섑븯떎(Lee et al., 2018). 븯吏留, EPO receptor 諛쒗쁽웾 遺꾩꽍 寃곌낵 GABA瑜 泥섎━븯吏 븡 洹몃9씤 G0 洹몃9뿉꽌뒗 NC뿉 鍮꾪빐 쑀쓽븯寃 媛먯냼븯쑝硫, GABA瑜 泥섎━븯뿬룄 利앷븯吏 븡븯떎. 씪諛섏쟻쑝濡 怨좎궛吏 媛숈씠 궛냼 솚寃쎌뿉 끂異쒖씠 릺硫 EPO 諛 EPO receptor쓽 諛쒗쁽씠 利앷븯뿬, 鍮덊삁뿉 긽쓳븯뒗 諛⑹뼱湲곗옉쓣 옉룞떆궓떎. 씠濡 씤빐 쟻삁援ъ 뿤紐④濡쒕퉰쓽 뼇쓣 利앷떆궎怨 옞젙쟻쑝濡 궛냼 슫諛 뒫젰쓣 뼢긽떆궓떎. 蹂 떎뿕 怨좎궛吏 媛숈 궛냼 솚寃쎄낵뒗 떎瑜닿쾶 븯猷 1떆媛꾩뵫 5씪媛, 留ㅼ슦 媛꾪뿉쟻쑝濡 궛냼 솚寃쎌뿉 끂異쒖떆耳곌린 븣臾몄뿉 EPO EPO receptor쓽 룞떆쟻씤 諛쒗쁽씠 씪뼱굹吏 븡븯쓣 寃껋쑝濡 깮媛곷맂떎.

EPO뒗 EPO receptor 寃고빀븯뿬 JAK-STAT (signal transducers and activators of transcription) 떊샇쟾떖뿉 쓽빐 議곗젅맂떎. Dimer 삎깭쓽 receptor뿉 EPO媛 寃고빀븯硫 닔슜꽦 떒諛깆쭏씤 JAK 寃고빀븯뿬, 떊샇쟾떖怨 쟾궗솢꽦씤옄씤 STAT쓽 솢꽦씠 씪뼱궃떎(Won et al., 2009). 蹂 떎뿕뿉꽌룄 GABA媛 EPO receptor쓽 諛쒗쁽뿉 쁺뼢쓣 誘몄튂吏 븡븯湲 븣臾몄뿉, JAK2쓽 諛쒗쁽 뿭떆 李⑥씠媛 뾾뿀뜕 寃껋쑝濡 솗씤릺뿀떎. 꽭룷媛 궛냼 긽깭뿉꽌 깮議댄븯怨 븘슂븳 궛냼瑜 뼸湲 쐞빐 hypoxia response element뒗 臾쇰줎 300뿬媛쒖쓽 쑀쟾옄뿉 쁺뼢쓣 誘몄튂硫, 씠 以묒뿉꽌룄 삁愿깮꽦珥됱쭊씤옄씤 VEGF EPO 諛 삉湲곗꽦 궗 愿젴 쑀쟾옄媛 媛옣 겙 쁺뼢쓣 諛쏄쾶 맂떎(Kimáková et al., 2017). 삉븳, 븫꽭룷媛 궛냼媛 遺議깊븳 솚寃쎌뿉 쟻쓳븷 닔 엳룄濡 븯뒗 HIF-1 떒諛깆쭏씠 諛쒓껄릺硫댁꽌 씠 愿젴맂 留ㅼ슦 留롮 臾명뿄뱾씠 蹂닿퀬릺怨 엳떎(Kaelin and Ratcliffe, 2008; Pugh and Ratcliffe, 2003). 蹂 떎뿕 寃곌낵 GABA쓽 泥섎━媛 EPO 諛쒗쁽 寃쏀뼢怨 룞씪븯寃 VEGF쓽 利앷뿉룄 쁺뼢쓣 誘몄튇 寃껋쑝濡 굹궗떎. HIF-1怨 HIF-2쓽 쑀쟾옄 諛쒗쁽遺꾩꽍 寃곌낵 CoCl2瑜 泥섎━븳 洹몃9뿉꽌 紐⑤몢 쑀쓽븳 利앷瑜 굹깉쑝硫, G500 洹몃9뿉꽌뒗 삤엳젮 HIF쓽 利앷瑜 뼲젣븯떎. 씪諛섏쟻쑝濡 HIF뒗 궛냼 솚寃쎌뿉 쓽븯뿬 諛쒗쁽릺怨 VEGF 諛쒗쁽 利앷뿉룄 쁺뼢쓣 誘몄튂뒗 寃껋쑝濡 븣젮졇 엳쑝硫, 洹 쇅쓽 hypoxia inducible gene뱾쓽 諛쒗쁽뿉룄 以묒슂븳 뿭븷쓣 븳떎(Kaelin and Ratcliffe, 2008). 븯吏留, breast cancer MCF-7 꽭룷 궡뿉 CoCl2瑜 닾뿬 썑 궛냼 솚寃쎌쓣 쑀룄븯쓣 寃쎌슦 쑀쟾옄 諛쒗쁽쓣 遺꾩꽍븯쓣 寃쎌슦 VEGF뒗 쑀쓽쟻쑝濡 利앷븯쑝굹, HIF-1 쑀쓽븳 李⑥씠瑜 뾾뿀떎(Qing et al., 2018). 삉븳, 꽭룷 궡뿉꽌 GABA媛 鍮꾩젙긽쟻씤 HIF 쑀쟾옄 諛쒗쁽웾쓣 뼲젣떆耳, 깮臾쇳븰쟻 빆긽꽦쓣 쑀吏떆궎젮뒗 옉슜씠씪怨 깮媛곷맂떎.

떊옣 議곗쭅 궡 EPO 쑀쟾옄 諛쒗쁽 諛 삁泥 궡 EPO 諛 RBC 닔移

떎뿕 醫낅즺 썑 떊옣 議곗쭅쓣 쟻異쒗븯뿬 룞씪遺遺꾩쓣 遺꾩꽍뿉 궗슜븯떎. 떊옣 議곗쭅쓽 EPO 諛쒗쁽遺꾩꽍 寃곌낵 NC 洹몃9뿉 鍮꾪빐 G0 洹몃9뿉꽌 빟 67.8諛곌 利앷븯떎(Fig. 3). 洹몄뿉 諛섑빐 G1, G5, G10 洹몃9뿉꽌뒗 媛곴컖 89.8±26.12%, 91.1±14.88%, 97.9±2.77%濡 留ㅼ슦 겕寃 媛먯냼븯떎.

Fig. 3. Effects of different concentrations of GABA on EPO and its related genes in rat kidney exposed to hypoxia. (A) Gene expression of EPO in kidney tissues, (B) EPO value of serum, (C) Red blood cell counts in whole blood. Data represent ration in mean ± SEM of experiment. Different letters indicate significant difference of the means (P<0.05). EPO, Erythropoietin.

룞臾쇱쓽 삁븸쓣 梨꾪삁븯뿬 삁泥 궡 EPO 닔移섎 遺꾩꽍븯떎. NC 洹몃9뿉 鍮꾪빐 G0 洹몃9뿉꽌 빟 89.3±21.53%쓽 닔移섎줈 利앷븯떎. 븯吏留 G0 洹몃9뿉 鍮꾪빐 G1, G5, G10 洹몃9뿉꽌 媛곴컖 60.5±22.08%, 51.3±34.74%, 57.4±8.70%쓽 닔移섎줈 쑀쓽븯寃 媛먯냼븯떎. 삉븳, 쟾삁쓣 씠슜븯뿬 쟻삁援 닔瑜 遺꾩꽍븯쑝굹 洹몃9 媛 쑀쓽븳 李⑥씠뒗 뾾뿀떎.

鍮덊삁씠 븘땶 긽깭뿉꽌 삁븸쓽 EPO 냽룄뒗 留ㅼ슦 궙吏留, 궛냼 뒪듃젅뒪뿉꽌뒗 빟 1,000諛곌 넂븘吏硫, 二쇰줈 떊옣 뵾吏덉뿉꽌 깮궛맂떎(Jacobson et al., 1957; Fisher et al., 1996). EPO뒗 삁븸쓽 궛냼냽룄뿉 뵲瑜 HIF 뵾뱶諛 湲곗옉쑝濡 議곗젅릺硫, 궛냼媛 엳뒗 솚寃쎌뿉꽌뒗 遺꾪빐맂떎. 蹂 떎뿕뿉꽌뒗 씛伊먯뿉寃 媛꾪뿉쟻쑝濡 궛냼 냽룄뿉 끂異쒖떆궎怨, GABA瑜 닾뿬븯뿬 EPO 쑀쟾옄쓽 諛쒗쁽웾쓣 遺꾩꽍븯떎. 궛냼 솚寃쎌뿉 끂異쒖떆궓 G0 洹몃9뿉꽌뒗 NC뿉 鍮꾪빐 諛쒗쁽웾씠 빟 68諛곕줈 利앷븯떎. 븯吏留 GABA 닾뿬洹몃9씤 G1, G5, G10뿉꽌뒗 꽭룷떎뿕怨 떖由 삤엳젮 EPO 諛쒗쁽웾쓣 겕寃 뼲젣븯떎. 삉븳, 삁泥 궡 EPO 닔移섎 遺꾩꽍븳 寃곌낵 NC 洹몃9뿉 鍮꾪빐 G0 洹몃9뿉꽌 쑀쓽븯寃 利앷븯怨, GABA 泥섎━洹몃9뿉꽌 떎떆 쑀쓽븯寃 媛먯냼븯떎. 씠뒗 留ㅼ슦 湲됯꺽븯寃 利앷븳 EPO 쑀쟾옄 諛쒗쁽쓣 뼲젣븯뿬, 옣湲곗쟻쑝濡 怨쇰룄븳 쟻삁援 닔쓽 利앷瑜 諛⑹븯뒗 湲곗쟾쓽 옉룞씠씪 깮媛곷맂떎. EPO뒗 젙긽 긽깭뿉꽌뒗 씪젙냽룄濡 遺꾨퉬릺뼱 삁븸냽룄瑜 쑀吏븯뒗뜲, 鍮꾩젙긽쟻씤 EPO쓽 利앷뒗 씠李⑥쟻씤 쟻삁援 利앷利앹쓣 씪쑝궗 닔 엳쑝硫 쓽븰쟻쑝濡 洹 썝씤쓣 젣嫄고븯뒗 寃껋씠 썝移숈씠떎(Lee and Arcasoy, 2015). 씛伊먯쓽 쟾삁뿉꽌 쟻삁援 닔쓽 蹂솕瑜 遺꾩꽍븯쑝굹, 쑀쓽븳 蹂솕뒗 솗씤릺吏 븡븯떎. 쟻삁援ъ쓽 깮꽦떒怨꾨뒗 怨⑥닔 以묒쓽 議고삁以꾧린꽭룷(Stem cell)쓽 遺꾪솕꽭룷씤 burst-forming unit-erythroid (BFU-E) colony-forming unit-erythroid (CFU-E)瑜 떒怨꾨 吏굹 proerythroblasts, erythroblasts瑜 嫄곗퀜 쟻삁援 깮꽦떆궓떎(Dulmovits et al., 2017). 씠 怨쇱젙뿉꽌 EPO媛 쁺뼢쓣 誘몄튂뒗 떒怨꾨뒗 BFU-E stage뿉꽌 쟻삁援 깮꽦 쟾떒怨꾩씤 erythroblast stage源뚯씠硫, 씠 떆媛꾩씠 빟 8씪 젙룄 냼슂맂떎. 蹂 떎뿕뿉꽌뒗 5씪媛 媛꾪뿉쟻쑝濡 궛냼 솚寃쎌뿉 끂異쒖떆耳곌린 븣臾몄뿉 삁泥 궡 EPO 닔移섍 넂븘議뚮떎 븯뜑씪룄 쟻삁援ъ쓽 닔媛 諛섏쓳븯湲곌퉴吏뒗 洹 湲곌컙씠 吏㏃븯쓣 寃껋쑝濡 삁긽븷 닔 엳떎.

蹂 뿰援ъ뿉꽌뒗 씤媛 媛꾩꽭룷 씛伊먯뿉寃 GABA瑜 닾뿬븯怨 궛냼 솚寃쎌뿉 끂異쒖떆궓 썑 EPO 洹몄 愿젴맂 쑀쟾옄쓽 諛쒗쁽 諛 삁泥 궡 EPO 닔移섎 遺꾩꽍븯떎. 媛꾩꽭룷뿉 CoCl2瑜 泥④븯뿬 궛냼 솚寃쎌쓣 議곗꽦 諛 끂異쒖떆耳곗쓣 븣, EPO媛 쑀쓽븯寃 利앷븯쑝硫, GABA 泥섎━洹몃9뿉꽌뒗 뜑슧 利앷븯떎. 븯吏留, EPO receptor EPO 湲곗쟾 넻濡쒖씤 JAK-2쓽 諛쒗쁽 GABA 泥④뿉 쓽븳 蹂솕媛 뾾뿀쑝硫, 궛냼쓽 諛섏쓳씤옄씤 삁愿깮꽦씤옄 VEGF GABA 泥④뿉 쓽빐 諛쒗쁽웾 利앷븯떎. 궛냼뿉 媛옣 癒쇱 諛섏쓳븯뒗 쑀쟾옄씤 HIF-1怨 HIF-2뒗 궛냼뿉 끂異쒕맂 紐⑤뱺 洹몃9뿉꽌 利앷븯쑝硫, G500 洹몃9뿉꽌뒗 삤엳젮 怨쇰컻쁽맂 HIF 쑀쟾옄 諛쒗쁽쓣 뼲젣떆耳곕떎.

씛伊먯뿉 궛냼냽룄瑜 젅諛섏쑝濡 以꾩씤 궛냼 솚寃쎌뿉 끂異쒖떆궓 썑 떊옣 議곗쭅쓣 쟻異 諛 EPO 쑀쟾옄 諛쒗쁽쓣 遺꾩꽍븯떎. G0 洹몃9뿉꽌 빟 68諛곗쓽 EPO 諛쒗쁽씠 利앷븯쑝굹, GABA 泥섎━洹몃9뿉꽌 삤엳젮 겙 룺쑝濡 뼲젣떆耳곕떎. 씛伊먯쓽 삁泥 궡 EPO 닔移 遺꾩꽍 寃곌낵 룞씪븳 寃쏀뼢쑝濡 솗씤릺뿀쑝굹, 쟻삁援 닔 遺꾩꽍뿉꽌뒗 쑀쓽븳 李⑥씠瑜 蹂댁씠吏 븡븯떎.

씛 伊먮 씪諛섏궗쑁 솚寃쎌뿉꽌 GABA瑜 닾뿬븯쓣 寃쎌슦, 삁泥 궡 EPO 諛 洹몄 愿젴맂 쑀쟾옄쓽 諛쒗쁽씠 利앷븯硫, 쟻삁援ъ쓽 닔 源뚯 쑀쓽븯寃 利앷븳떎뒗 蹂닿퀬媛 엳떎(Park et al., 2020). 蹂 뿰援ъ뿉꽌뒗 씛 伊먮 떎젣 궛냼 솚寃쎌뿉 븯猷 1떆媛, 5씪媛 끂異쒖쓣 떆耳곗쑝硫, 留ㅼ슦 겕寃 EPO 쑀쟾옄쓽 諛쒗쁽씠 利앷븳 寃껋쓣 솗씤븯떎. 씠뿉, GABA瑜 닾뿬븯쓣 寃쎌슦 삤엳젮 EPO 쑀쟾옄 諛쒗쁽쓣 뼲젣븯뒗 寃쏀뼢씠 굹궗쑝硫, 떎젣 삁泥 궡 EPO 닔移섎룄 寃쏀뼢씠 씪移섑븯떎. 蹂 떎뿕 Hep3 B 꽭룷뿉 CoCl2濡 쑀룄븳 궛냼 솚寃쎈낫떎 뜑 怨쇰룄븳 쑀룄떎뿕씠硫, 떎젣 궛냼냽룄瑜 궙異 in vivo 떎뿕쑝濡쒖뜥 泥대궡 샇瑜대が 諛섏쓳씠 湲됯꺽엳 씪뼱궇 寃껋쑝濡 삁긽맂떎. GABA뒗 理쒓렐 뿰援щ 넻빐 옣떊寃쎄퀎(Enteric nervous system)瑜 鍮꾨’븳 留먯큹떊寃 벑 떊泥 쟾諛섏뿉꽌 떊泥 빆꽦꽦 쑀吏뿉 以묒슂븳 뿭븷쓣 븯怨 엳떎뒗 궗떎씠 洹쒕챸릺怨 엳쑝硫(Arne and Helle, 2007), 蹂 뿰援 寃곌낵뿉꽌룄 湲됯꺽븳 샇瑜대が 蹂솕뿉 쓳븯湲 쐞븳 GABA쓽 빆긽꽦 湲곗옉씠 諛쒗쁽븳 寃껋쑝濡 뙋떒맂떎.

蹂 뿰援ъ뿉꽌 二쇰ぉ븷 寃껋 GABA 泥④뿉 쓽빐 꽭룷떎뿕怨 룞臾쇱떎뿕쓽 EPO 諛쒗쁽씠 諛섎 寃쏀뼢쑝濡 솗씤릺뿀쑝硫, 씠뒗 깮泥댁쓽 議곗쭅꽭룷瑜 遺꾨━븯뿬 듅젙 臾쇱쭏 삉뒗 솚寃쎌뿉 뼱뼸寃 諛섏쓳븯뒗媛瑜 궡뵾뒗 꽭룷떎뿕怨쇰뒗 떎瑜닿쾶 씤媛꾧낵 怨듯넻쟻씤 깮泥댄븰쟻 諛섏쓳씠 留ㅼ슦 쑀궗븳 룞臾쇱떎뿕씠湲 븣臾몄씠씪怨 깮媛곷맂떎.

理쒖쥌쟻쑝濡 궛냼 긽깭뿉꽌 GABA媛 erythropoiesis뿉 誘몄튂뒗 쁺뼢쓣 遺꾩꽍븯쑝硫, 뼢썑 슜삁꽦 鍮덊삁 諛 湲고 鍮덊삁 紐⑤뜽뿉꽌 GABA쓽 EPO 깮궛 뿰援 諛 깮由ш린뒫 룊媛媛 닔諛섎릺뼱빞 븷 寃껋씠떎.

ACKNOWLEDGEMENT

This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (No. 2018R1C1B5086313).

CONFLICT OF INTEREST

The authors have declared no conflict of interest.

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