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Article(id=1322218754960905189, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322218723616862544, articleNumber=null, orderNo=null, doi=10.16016/j.2097-0927.202501053, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1738425600000, receivedDateStr=2025-02-02, revisedDate=1744041600000, revisedDateStr=2025-04-08, acceptedDate=null, acceptedDateStr=null, onlineDate=1793171116819, onlineDateStr=2026-10-28, pubDate=1749916800000, pubDateStr=2025-06-15, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793171116819, onlineIssueDateStr=2026-10-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793171116819, creator=13701087609, updateTime=1793171116819, updator=13701087609, issue=Issue{id=1322218723616862544, tenantId=1146029695717560320, journalId=1319373162502258839, year='2025', volume='47', issue='11', pageStart='1145', pageEnd='1242', issueExtLink='null', onlineDate='null', pubDate='1749916800000', pubDateStr='2025-06-15', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1793171109346, creator='13701087609', updateTime=1793325423536, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1322865964295766226, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322218723616862544, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1322865964295766227, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322218723616862544, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1145, endPage=1154, ext={EN=ArticleExt(id=1322218756647015398, articleId=1322218754960905189, tenantId=1146029695717560320, journalId=1319373162502258839, language=EN, title=Oxoglutarate dehydrogenase-L regulates mitochondrial metabolism reprogramming of renal tubular epithelial cells to alleviate renal fibrosis, columnId=1320434418116837551, journalTitle=Journal of Army Medical University, columnName=Basic Medicine, runingTitle=null, highlight=null, articleAbstract=
Objective‍

To investigate the role and underlying mechanisms of oxoglutarate dehydrogenase-L (OGDHL) in renal fibrosis.

Methods‍

Twelve male wild-type C57BL/6J mice (8 weeks old, weighting about 25 g) were randomly divided into control group and model group (n=6). A mouse model of renal fibrosis was established by unilateral ureteral obstruction (UUO). HE staining, immunofluorescence assay, and immunohistochemical and Masson staining were applied to assess the extent of renal fibrosis. Human kidney-2 proximal tubule cell line (HK-2) were randomly divided into blank plasmid group (Vector), OGDHL overexpression group (OGDHL OE), blank plasmid + TGF-β1 treatment group (TGF-β1+Vector), TGF-β1 treatment and OGDHL overexpression group (TGF-β1+OGDHL OE). Transmission electron microscopy (TEM) was employed to observe mitochondrial morphology. RT-qPCR, Western blotting and immunofluorescence assay were used to detect the expression levels of OGDHL and mitochondrial metabolism-related genes. Adenosine triphosphate (ATP) level, oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and other mitochondrial metabolism-related indicators were detected with corresponding reagent kits and Agilent Seahorse.

Results‍

UUO operation resulted in obvious thinning of the renal cortex, significant hydronephrosis. HE staining revealed that tubular atrophy accompanied by dilated tubular lumens in the kidneys. Immunofluorescence, immunohistochemical and Masson staining showed obvious renal fibrosis after UUO operation. In the mouse model of renal fibrosis, the expression of OGDHL was decreased by 82.9% at mRNA level (P<0.001) and 81.9% at protein level (P<0.001), the production of mitochondrial ATP was reduced by 0.970±0.151 µmol/L (P<0.01), and notable damaged mitochondrial structure was observed, with maximum breathing capacity decreased by 25.260±1.920 pmol/min (P<0.001), expression levels of fatty acid oxidation-related genes were declined by 50.2% (P<0.05), while glycolysis was enhanced, with the genes related to glycolysis increased by 2.5 times when compared with those in the control group (P<0.05). After OGDHL overexpression, mitochondrial morphological damage was significantly improved, ATP production was increased by 0.980±0.090 µmol/L (P<0.05), with significantly alleviated energy metabolism disorder and renal fibrosis (P<0.05).

Conclusion‍

OGDHL regulates mitochondrial metabolic reprogramming of renal tubular epithelial cells to alleviate fibrosis, suggesting that OGDHL may be a new therapeutic target for renal fibrosis.

, authors=Yingxian YANG, Yinghui HUANG, Jinghong ZHAO, authorsList=Yingxian YANG, Yinghui HUANG, Jinghong ZHAO, authorCompany=null, correspAuthors=Jinghong ZHAO, authorNote=null, correspAuthorsNote=null, copyrightStatement=© 2025 Journal of Army Medical University, copyrightOwner=Editorial Office of Journal of Army Medical University, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1322218757955638255, articleId=1322218754960905189, tenantId=1146029695717560320, journalId=1319373162502258839, language=CN, title=氧戊二酸脱氢酶L调控肾小管上皮细胞线粒体代谢重编程缓解肾纤维化, columnId=1322185528879993170, journalTitle=陆军军医大学学报, columnName=基础医学, runingTitle=null, highlight=null, articleAbstract=
目的

探究氧戊二酸脱氢酶L（oxoglutarate dehydrogenase-L，OGDHL）在肾纤维化中的作用及其机制。

方法

采用随机数字表法将12只雄性野生型C57BL/6J小鼠（8周龄，体质量约25 g）分为对照组与单侧输尿管梗阻（unilateral ureteral obstruction，UUO）组（n=6），通过UUO建立小鼠肾纤维化模型。采用苏木精-伊红（hematoxylin and eosin，HE）染色、免疫荧光染色、免疫组织化学染色、Masson染色检测模型的纤维化程度；培养人近端小管上皮细胞系-2（human kidney-2 proximal tubule cell line，HK-2），分为对照质粒空载体组（Vector组）、过表达OGDHL组（OGDHL OE组）、TGF-β1+对照质粒空载体组（TGF-β1+Vector组）、TGF-β1+过表达OGDHL组（TGF-β1+OGDHL OE组）4组，通过透射电镜观察线粒体形态；通过RT-qPCR、Western blot、免疫荧光染色检测OGDHL及线粒体代谢相关基因的表达水平，并通过试剂盒检测三磷酸腺苷（adenosine triphosphate，ATP）水平，通过安捷伦Seahorse细胞代谢分析仪检测氧耗率（oxygen consumption rate，OCR）、细胞外酸化率（extracellular acidification rate，ECAR）等线粒体代谢相关指标。

结果

UUO术后肾脏肾皮质明显变薄、肾积水显著。HE染色显示肾小管萎缩、管腔扩大；免疫荧光、免疫组织化学染色、Masson染色显示纤维化明显。肾纤维化时，肾脏OGDHL的表达在mRNA水平下降82.9%（P<0.001），在蛋白水平下降81.9%（P<0.001）。线粒体ATP生成减少（0.970±0.151）µmol/L（P<0.01），线粒体结构损伤，最大呼吸能力降低（25.260±1.920） pmol/min（P<0.001），脂肪酸氧化相关基因下降50.2%（P<0.05），糖酵解增强，ECAR上升，糖酵解相关基因上升为对照组的2.5倍（P<0.05）。OGDHL过表达后线粒体形态学损伤显著改善，ATP生成增加（0.980±0.090） µmol/L（P<0.001），能量代谢障碍显著缓解，肾纤维化明显减轻（P<0.05）。

结论

OGDHL调控线粒体代谢重编程从而缓解肾小管上皮细胞的纤维化，提示OGDHL可能成为肾纤维化治疗的新靶点。

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赵景宏，E-mail：
ZHAO Jinghong，E-mail：
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Physiol Rev，2023，103（4）：2827-2872., articleTitle=Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis, refAbstract=null), Reference(id=1322218766369411114, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, doi=10.16016/i.1000-5404.201907139, pmid=null, pmcid=null, year=2020, volume=42, issue=1, pageStart=50, pageEnd=58, url=null, language=null, rfNumber=22, rfOrder=21, authorNames=段晨阳, 向鑫明, 匡磊, journalName=第三军医大学学报, refType=null, unstructuredReference=段晨阳，向鑫明，匡磊，等. 活化Drpl介导谷胱甘肽代谢调节失血性休克后线粒体功能的研究［J］. 第三军医大学学报，2020，42（1）：50-58., articleTitle=活化Drpl介导谷胱甘肽代谢调节失血性休克后线粒体功能的研究, refAbstract=null), Reference(id=1322218766449102891, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, doi=10.16016/i.1000-5404.201907139, pmid=null, pmcid=null, year=2020, volume=42, issue=1, pageStart=50, pageEnd=58, url=null, language=null, rfNumber=22, rfOrder=22, authorNames=DUAN C Y, XIANG X M, KUANG L, journalName=J Third Mil Med Univ, refType=null, unstructuredReference=DUAN C Y，XIANG X M，KUANG L，et al. Role of activated dynamin-related protein 1-mediated glutathione metabolism in regulation of mitochondrial dysfunction after hemorrhagic shock［J］. J Third Mil Med Univ，2020，42（1）：50-58., articleTitle=Role of activated dynamin-related protein 1-mediated glutathione metabolism in regulation of mitochondrial dysfunction after hemorrhagic shock, refAbstract=null), Reference(id=1322218766570737708, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, doi=10.3390/biom9040141, pmid=null, pmcid=null, year=2019, volume=9, issue=4, pageStart=141, pageEnd=null, url=null, language=null, rfNumber=23, rfOrder=23, authorNames=MARTÍNEZ-KLIMOVA E, APARICIO-TREJO O E, TAPIA E, journalName=Biomolecules, refType=null, unstructuredReference=MARTÍNEZ-KLIMOVA E，APARICIO-TREJO O E，TAPIA E，et al. Unilateral ureteral obstruction as a model to investigate fibrosis-attenuating treatments［J］. Biomolecules，2019，9（4）：141., articleTitle=Unilateral ureteral obstruction as a model to investigate fibrosis-attenuating treatments, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1322218758224073712, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, xref=1, ext=[AuthorCompanyExt(id=1322218758232462321, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, companyId=1322218758224073712, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Nephrology，Chongqing Key Laboratory for Prevention and Treatment of Kidney Diseases，Chongqing Clinical Research Center of Kidney and Urology Diseases，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China), AuthorCompanyExt(id=1322218758240850930, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, companyId=1322218758224073712, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军军医大学（第三军医大学）第二附属医院肾内科，重庆市肾脏病防治重点实验室，重庆市肾病与泌尿系统疾病临床医学研究中心，重庆)])], figs=[ArticleFig(id=1322218761541767178, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, language=EN, label=null, caption=null, figureFileSmall=2/V91mZ3zB6NUyzatEYsug==, figureFileBig=Um8g0tLWMGPe4aC4d1clbw==, tableContent=null), ArticleFig(id=1322218761621458955, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, language=CN, label=图1, caption=肾纤维化模型的建立与验证（n=3，x¯±s）

A：UUO术后肾脏大体外观肾积水情况；B：UUO术后肾脏皮质的HE染色； C：UUO术后纤维化标志物FN免疫组织化学染色和α-SMA免疫荧光染色图；C：UUO术后肾脏皮质Masson染色图；E、F：Western blot检测体内UUO、体外TGF-β1诱导的纤维化表型转化细胞中α-SMA和FN的蛋白表达水平　a：P<0.001

, figureFileSmall=2/V91mZ3zB6NUyzatEYsug==, figureFileBig=Um8g0tLWMGPe4aC4d1clbw==, tableContent=null), ArticleFig(id=1322218761873117196, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, language=EN, label=null, caption=null, figureFileSmall=L4T/k/RHA9p3hwmeCWVBBg==, figureFileBig=e4sGFVqig3vJWuyuSYE4wA==, tableContent=null), ArticleFig(id=1322218761952808973, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, language=CN, label=图2, caption=肾纤维化中OGDHL的表达水平检测（n=3，x¯±s）

a：P<0.001

, figureFileSmall=L4T/k/RHA9p3hwmeCWVBBg==, figureFileBig=e4sGFVqig3vJWuyuSYE4wA==, tableContent=null), ArticleFig(id=1322218762045083662, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, language=EN, label=null, caption=null, figureFileSmall=AEg3fFLAWx3sK74a71srdw==, figureFileBig=9Dnts7sOv6kchxYJwZE4Ww==, tableContent=null), ArticleFig(id=1322218762112192527, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, language=CN, label=图3, caption=肾纤维化中线粒体代谢的重编程（n=3，x¯±s）

a：P<0.01，b：P<0.05，c：P<0.001

, figureFileSmall=AEg3fFLAWx3sK74a71srdw==, figureFileBig=9Dnts7sOv6kchxYJwZE4Ww==, tableContent=null), ArticleFig(id=1322218762225438736, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, language=EN, label=null, caption=null, figureFileSmall=/WMuCN6PP0DoaxA9S7LYrA==, figureFileBig=NIDJxwjTeQLeBCYNuvCtcA==, tableContent=null), ArticleFig(id=1322218762317713425, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, language=CN, label=图4, caption=过表达OGDHL缓解的线粒体代谢重编程

a：P<0.001，b：P<0.01，c：P<0.05

, figureFileSmall=/WMuCN6PP0DoaxA9S7LYrA==, figureFileBig=NIDJxwjTeQLeBCYNuvCtcA==, tableContent=null), ArticleFig(id=1322218762389016594, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
基因名称引物序列（5′→3′）
OGDHL（人）上游：GTGAAGGTGACAGCAGTCGGTT
下游：GTGAAGGTGACAGCAGTCGGTT
β-actin（人）上游：AACAGTCCGCCTAGAAGCAC
下游：CGTTGACATCCGTAAAGACC
PPARα（人）上游：CTGCAGAGCAACCATCCAGA
下游：GCAAATCCCTGCTCTCCTGT
CPT1a（人）上游：GTCCTGCAACTTTGTGCTGG
下游：CAGGTGCTGGTGCTTTTCAC
CPT2（人）上游：CAGCACAGCATCGTACCCA
下游：TCCCAATGCCGTTCTCAAAAT
ACOX1（人）上游：TAACTTCCTCACTCGAAGCCA
下游：AGTTCCATGACCCATCTCTGTC
HK1（人）上游：GCTCTCCGATGAAACTCTCATAG
下游：GGACCTTACGAATGTTGGCAA
HK2（人）上游：GAGCCACCACTCACCCTACT
下游：CCAGGCATTCGGCAATGTG
PFKP（人）上游：GCATGGGTATCTACGTGGGG
下游：CTCTGCGATGTTTGAGCCTC
PKM（人）上游：ATGTCGAAGCCCCATAGTGAA
下游：TGGGTGGTGAATCAATGTCCA
OGDHL（小鼠）上游：GCTCTACGACTGCAACTGGA
下游：CCGGACACCATCTGGTCAAA
β-actin（小鼠）上游：AACAGTCCGCCTAGAAGCAC
下游：CGTTGACATCCGTAAAGACC
), ArticleFig(id=1322218762481291283, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218754960905189, language=CN, label=表1, caption=

目的基因、内参基因、脂肪酸氧化及糖酵解相关基因的引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因名称引物序列（5′→3′）
OGDHL（人）上游：GTGAAGGTGACAGCAGTCGGTT
下游：GTGAAGGTGACAGCAGTCGGTT
β-actin（人）上游：AACAGTCCGCCTAGAAGCAC
下游：CGTTGACATCCGTAAAGACC
PPARα（人）上游：CTGCAGAGCAACCATCCAGA
下游：GCAAATCCCTGCTCTCCTGT
CPT1a（人）上游：GTCCTGCAACTTTGTGCTGG
下游：CAGGTGCTGGTGCTTTTCAC
CPT2（人）上游：CAGCACAGCATCGTACCCA
下游：TCCCAATGCCGTTCTCAAAAT
ACOX1（人）上游：TAACTTCCTCACTCGAAGCCA
下游：AGTTCCATGACCCATCTCTGTC
HK1（人）上游：GCTCTCCGATGAAACTCTCATAG
下游：GGACCTTACGAATGTTGGCAA
HK2（人）上游：GAGCCACCACTCACCCTACT
下游：CCAGGCATTCGGCAATGTG
PFKP（人）上游：GCATGGGTATCTACGTGGGG
下游：CTCTGCGATGTTTGAGCCTC
PKM（人）上游：ATGTCGAAGCCCCATAGTGAA
下游：TGGGTGGTGAATCAATGTCCA
OGDHL（小鼠）上游：GCTCTACGACTGCAACTGGA
下游：CCGGACACCATCTGGTCAAA
β-actin（小鼠）上游：AACAGTCCGCCTAGAAGCAC
下游：CGTTGACATCCGTAAAGACC
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氧戊二酸脱氢酶L调控肾小管上皮细胞线粒体代谢重编程缓解肾纤维化
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杨应现 , 黄英辉 , 赵景宏
陆军军医大学学报 | 基础医学 2025,47(11): 1145-1154
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陆军军医大学学报 |基础医学 2025 , 47 (11) : 1145 -1154
氧戊二酸脱氢酶L调控肾小管上皮细胞线粒体代谢重编程缓解肾纤维化
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杨应现, 黄英辉, 赵景宏
作者信息
  • 1陆军军医大学（第三军医大学）第二附属医院肾内科，重庆市肾脏病防治重点实验室，重庆市肾病与泌尿系统疾病临床医学研究中心，重庆
通讯作者:
赵景宏，E-mail：
ZHAO Jinghong，E-mail：
Oxoglutarate dehydrogenase-L regulates mitochondrial metabolism reprogramming of renal tubular epithelial cells to alleviate renal fibrosis
Yingxian YANG, Yinghui HUANG, Jinghong ZHAO
Affiliations
  • 1Department of Nephrology，Chongqing Key Laboratory for Prevention and Treatment of Kidney Diseases，Chongqing Clinical Research Center of Kidney and Urology Diseases，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China
出版时间: 2025-06-15 doi: 10.16016/j.2097-0927.202501053
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摘要
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目的

探究氧戊二酸脱氢酶L（oxoglutarate dehydrogenase-L，OGDHL）在肾纤维化中的作用及其机制。

方法

采用随机数字表法将12只雄性野生型C57BL/6J小鼠（8周龄，体质量约25 g）分为对照组与单侧输尿管梗阻（unilateral ureteral obstruction，UUO）组（n=6），通过UUO建立小鼠肾纤维化模型。采用苏木精-伊红（hematoxylin and eosin，HE）染色、免疫荧光染色、免疫组织化学染色、Masson染色检测模型的纤维化程度；培养人近端小管上皮细胞系-2（human kidney-2 proximal tubule cell line，HK-2），分为对照质粒空载体组（Vector组）、过表达OGDHL组（OGDHL OE组）、TGF-β1+对照质粒空载体组（TGF-β1+Vector组）、TGF-β1+过表达OGDHL组（TGF-β1+OGDHL OE组）4组，通过透射电镜观察线粒体形态；通过RT-qPCR、Western blot、免疫荧光染色检测OGDHL及线粒体代谢相关基因的表达水平，并通过试剂盒检测三磷酸腺苷（adenosine triphosphate，ATP）水平，通过安捷伦Seahorse细胞代谢分析仪检测氧耗率（oxygen consumption rate，OCR）、细胞外酸化率（extracellular acidification rate，ECAR）等线粒体代谢相关指标。

结果

UUO术后肾脏肾皮质明显变薄、肾积水显著。HE染色显示肾小管萎缩、管腔扩大；免疫荧光、免疫组织化学染色、Masson染色显示纤维化明显。肾纤维化时，肾脏OGDHL的表达在mRNA水平下降82.9%（P<0.001），在蛋白水平下降81.9%（P<0.001）。线粒体ATP生成减少（0.970±0.151）µmol/L（P<0.01），线粒体结构损伤，最大呼吸能力降低（25.260±1.920） pmol/min（P<0.001），脂肪酸氧化相关基因下降50.2%（P<0.05），糖酵解增强，ECAR上升，糖酵解相关基因上升为对照组的2.5倍（P<0.05）。OGDHL过表达后线粒体形态学损伤显著改善，ATP生成增加（0.980±0.090） µmol/L（P<0.001），能量代谢障碍显著缓解，肾纤维化明显减轻（P<0.05）。

结论

OGDHL调控线粒体代谢重编程从而缓解肾小管上皮细胞的纤维化，提示OGDHL可能成为肾纤维化治疗的新靶点。

肾纤维化  /  氧戊二酸脱氢酶L  /  线粒体代谢重编程  /  肾小管上皮细胞
Objective‍

To investigate the role and underlying mechanisms of oxoglutarate dehydrogenase-L (OGDHL) in renal fibrosis.

Methods‍

Twelve male wild-type C57BL/6J mice (8 weeks old, weighting about 25 g) were randomly divided into control group and model group (n=6). A mouse model of renal fibrosis was established by unilateral ureteral obstruction (UUO). HE staining, immunofluorescence assay, and immunohistochemical and Masson staining were applied to assess the extent of renal fibrosis. Human kidney-2 proximal tubule cell line (HK-2) were randomly divided into blank plasmid group (Vector), OGDHL overexpression group (OGDHL OE), blank plasmid + TGF-β1 treatment group (TGF-β1+Vector), TGF-β1 treatment and OGDHL overexpression group (TGF-β1+OGDHL OE). Transmission electron microscopy (TEM) was employed to observe mitochondrial morphology. RT-qPCR, Western blotting and immunofluorescence assay were used to detect the expression levels of OGDHL and mitochondrial metabolism-related genes. Adenosine triphosphate (ATP) level, oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and other mitochondrial metabolism-related indicators were detected with corresponding reagent kits and Agilent Seahorse.

Results‍

UUO operation resulted in obvious thinning of the renal cortex, significant hydronephrosis. HE staining revealed that tubular atrophy accompanied by dilated tubular lumens in the kidneys. Immunofluorescence, immunohistochemical and Masson staining showed obvious renal fibrosis after UUO operation. In the mouse model of renal fibrosis, the expression of OGDHL was decreased by 82.9% at mRNA level (P<0.001) and 81.9% at protein level (P<0.001), the production of mitochondrial ATP was reduced by 0.970±0.151 µmol/L (P<0.01), and notable damaged mitochondrial structure was observed, with maximum breathing capacity decreased by 25.260±1.920 pmol/min (P<0.001), expression levels of fatty acid oxidation-related genes were declined by 50.2% (P<0.05), while glycolysis was enhanced, with the genes related to glycolysis increased by 2.5 times when compared with those in the control group (P<0.05). After OGDHL overexpression, mitochondrial morphological damage was significantly improved, ATP production was increased by 0.980±0.090 µmol/L (P<0.05), with significantly alleviated energy metabolism disorder and renal fibrosis (P<0.05).

Conclusion‍

OGDHL regulates mitochondrial metabolic reprogramming of renal tubular epithelial cells to alleviate fibrosis, suggesting that OGDHL may be a new therapeutic target for renal fibrosis.

‍renal fibrosis  /  oxoglutarate dehydrogenase-L  /  mitochondrial metabolism reprogramming  /  renal tubular epithelial cells
杨应现, 黄英辉, 赵景宏. 氧戊二酸脱氢酶L调控肾小管上皮细胞线粒体代谢重编程缓解肾纤维化. 陆军军医大学学报, 2025 , 47 (11) : 1145 -1154 . DOI: 10.16016/j.2097-0927.202501053
Yingxian YANG, Yinghui HUANG, Jinghong ZHAO. Oxoglutarate dehydrogenase-L regulates mitochondrial metabolism reprogramming of renal tubular epithelial cells to alleviate renal fibrosis[J]. Journal of Army Medical University, 2025 , 47 (11) : 1145 -1154 . DOI: 10.16016/j.2097-0927.202501053
正文
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慢性肾脏病是全球主要的致死因素之一，其中肾纤维化是进展性慢性肾脏病的最终结局［1］，同时也是导致肾功能衰竭的关键因素。然而，目前针对肾纤维化的治疗方法效果有限，现有治疗主要依赖于透析和非特异性药物，这些治疗只能延缓疾病的进展，无法有效逆转已发生的肾纤维化［2-3］。因此，迫切需要识别新的治疗靶点并开发更为有效的治疗策略，以达到阻止或逆转肾纤维化进展的治疗目的。
肾纤维化的主要特征包括肾小管上皮细胞的萎缩、细胞外基质的持续积累、成纤维细胞的活化及免疫细胞的浸润［4-5］。肾小管上皮细胞作为肾脏中数量最多的细胞，在肾纤维化的发生和慢性肾脏病的发展中起着重要作用［6-7］。在正常生理条件下，肾皮质中的肾小管上皮细胞通过线粒体中的脂肪酸氧化途径产生三磷酸腺苷（adenosine triphosphate，ATP），以维持细胞的能量需求［8-10］。然而，在某些病理状态下，线粒体结构遭到破坏，氧化磷酸化过程受阻，进而激活无氧糖酵解途径［11］。肾纤维化时，肾小管上皮细胞经历代谢重编程，线粒体代谢从主要的脂肪酸氧化过渡为糖酵解，导致ATP产生减少，线粒体代谢能力下降，这些变化与肾纤维化的加重密切相关。虽然已有大量研究表明线粒体代谢障碍在肾纤维化中的作用，但关于这一机制的具体机制仍未完全阐明［1，12］。因此，深入研究肾小管上皮细胞中线粒体代谢障碍对肾纤维化的影响，可能为开发新的治疗策略提供重要线索。
氧戊二酸脱氢酶L（oxoglutarate dehydrogenase-L，OGDHL）是氧戊二酸脱氢酶（oxoglutarate dehydrogenase，OGDH）的同工酶，是氧戊二酸脱氢酶复合体（oxoglutarate dehydrogenase complex，OGDHC）发挥功能的主要限速亚基。OGDHC是三羧酸循环中的一种限速酶，可以将 α-酮戊二酸转化为琥珀酰辅酶A［13］。因此，OGDHL表达的改变可能通过调控线粒体代谢从而参与肾纤维化过程，然而，OGDHL在肾纤维化中的具体作用及其机制亟待探索。本研究旨在通过建立体内和体外肾纤维化模型并检测线粒体代谢相关指标，探究OGDHL在肾纤维化过程中的作用及其调控肾小管上皮细胞线粒体代谢的分子机制，为慢性肾脏病肾纤维化的治疗提供新的思路和靶点。
1　材料与方法
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1.1　材料与实验试剂
野生（wild type，WT）C57BL/6J小鼠购自中国北京华阜康生物科技公司；人近端小管上皮细胞系-2（human kidney-2 proximal tubule cell line，HK-2）购自美国ATCC细胞库；RNA提取试剂盒购自中国碧云天公司；β-actin抗体（T200068-8F10）购自中国成都正能公司；LipofectamineTM 3000转染试剂购自美国Thermo Fisher Scientific公司；纤连蛋白（fibronectin，FN）抗体（ab2413）购自英国Abcam公司；α-平滑肌肌动蛋白（α-smooth muscle actin，α-SMA）抗体（14395-1-AP）购自中国武汉三鹰公司；Masson染色试剂盒（Cat#G1346）购自中国北京索莱宝生物公司；OGDHL抗体（17110-1-AP）、重组人TGF-β1蛋白（HZ-1011）购自中国武汉三鹰公司；实时荧光定量PCR试剂盒（HY-K0501）、反转录试剂盒（HY-K0501A）购自美国MCE公司；OGDHL过表达质粒购自中国柏欧尼生物技术有限公司；ATP测定试剂盒（A095-1-1）购自中国南京建成生物工程研究所。
1.2　HK-2细胞的培养与分组
用含有10%胎牛血清的DMEM/F12培养基在恒温37 ℃、含有5%CO2的培养箱中培养HK-2细胞。观察HK-2细胞形态及密度，当细胞形态正常且无明显皱缩或者纤维化，细胞密度达到约50%时，用无血清培养基同步化处理12 h。对于纤维化验证实验，将细胞分为对照组和TGF-β1组。对于过表达OGDHL来缓解线粒体代谢的实验，将细胞分为4组进行不同的处理：对照质粒空载体组（Vector组）、过表达OGDHL组（OGDHL OE组），TGF-β1+对照质粒空载体组（TGF-β1+Vector组）、TGF-β1+过表达OGDHL组（TGF-β1+OGDHL OE组）。Vector组用正常的无特殊处理的含血清培养基培养并转染空载体；OGDHL OE组转染过表达OGDHL质粒；TGF-β1组用10 ng/mL TGF-β1处理HK-2细胞诱导纤维化；TGF-β1+OGDHL OE组在TGF-β1处理细胞前24 h转染OGDHL过表达质粒，用TGF-β1处理转染OGDHL过表达质粒的细胞24 h；各组提取蛋白质或RNA进行相关检测。
1.3　小鼠肾脏单侧输尿管梗阻（unilateral ureteral obstruction ，UUO）模型的建立
将12只雄性8周龄实验小鼠（体质量约25 g）按随机数字表法分为2组（对照组和UUO组），每组6只，接着对小鼠进行UUO手术。在UUO模型中，为防止逆行性尿路感染，将左侧输尿管分开，用3-0线完全结扎，在小鼠镇静后于结扎线之间切断。除输尿管结扎外，对照组均行相同手术操作。所有的手术操作均已经陆军军医大学第二附属医院动物伦理委员会审批通过（AMUWEC20224500），所有小鼠饲养在25 ℃、40%~70%湿度的SPF级动物饲养笼子中，不限制食物和水的获取，所有手术操作通过1%戊巴比妥麻醉以减轻疼痛和折磨，监测UUO术后出现预期的肾积水情况，监测时间点为术后14 d。
1.4　ATP的检测
依据ATP测定试剂盒说明书，在细胞中加入200 µL细胞裂解液裂解细胞30 min，4 ℃、12 000×g离心5 min，离心后置于冰上，配制不同浓度标准品后，将ATP检测试剂用稀释液稀释至ATP检测工作液，在黑色避光的96孔细胞培养板中每孔加入100 µL ATP检测工作液，室温静置5 min，取20 µL不同浓度标准品（0.01、0.03、0.10、0.30、1.00、3.00、10.00 µmol/L）加入标准孔，取20 µL各待测样本加入样本孔，间隔10 s后化学发光仪（酶标仪）检测相对发光强度（relative light unit，RLU）值，根据各标准孔数值做出标准曲线，根据待测样本的检测数值，计算出每个待测样本的ATP 含量。
1.5　Western blot检测
取HK-2细胞和1/6肾组织分别加入100 μL RIPA蛋白裂解液，用匀浆机匀浆，冰上放置30 min，以4 ℃、12 000×g离心15min后，取上清液转移至新的离心管中，用BCA试剂盒测量蛋白浓度，并加入适当裂解液使总蛋白浓度相等，加热制成可电泳的蛋白样本，冻存于冰箱。根据10%凝胶配制体系制备凝胶，各孔中加入10 μL蛋白样品，电泳仪设置：恒压75 V运行30 min，随后125 V运行60 min，电转：恒流280 mA，时间为130 min，按照负极-凝胶-PVDF转至PVDF膜上；在37 ℃摇床上用封闭液封闭1 h；按照1∶1 000稀释Western blot抗体，4 ℃孵育过夜。次日回收抗体，用适量TBST洗涤3次，每次10 min，山羊抗小鼠或免IgG二抗（英国Abcam公司，1∶2 000）37 ℃孵育1 h。TBST 洗膜3次后于Bio-Rad凝胶成像仪中进行显色，保存图像。
1.6　RT-qPCR检测
用RNA提取试剂盒提取适量细胞或组织RNA后测定RNA浓度，根据反转录试剂盒操作步骤反转录成cDNA。使用MCE SYBR Green qPCR Master Mix扩增cDNA。引物序列由华大基因公司设计合成，序列见表1。
1.7　免疫组织化学染色
取切片脱水，65 ℃下在烤箱内烘烤切片30 min，组织切片浸泡在二甲苯溶液及浓度分别为100%、95%、80%、70%的乙醇溶液中各5 min，脱蜡，碱性柠檬酸盐修复液高温高压修复15 min，过氧化物酶阻断剂阻断10 min，37 ℃封闭30 min，孵育抗体4 ℃过夜，次日37 ℃复温1 h，37 ℃二抗孵育1 h，DAB显色，苏木素细胞核染色。普通显微镜下观察组织化学染色结果，并采集图像。
1.8　免疫荧光染色
取切片脱水，65 ℃下在烤箱内烘烤切片30 min，组织切片浸泡在二甲苯溶液及浓度分别为100%、95%、80%、70%的乙醇溶液中各5 min脱蜡，碱性柠檬酸盐修复液高温高压修复15 min，37 ℃封闭30 min，孵育抗体4 ℃过夜，次日37 ℃复温1 h，37 ℃二抗孵育1 h，DAPI细胞核染色10 min。共聚焦显微镜下观察免疫荧光染色结果，并采集图像。
1.9　透射电镜观察
切取约1 mm3肾组织或HK-2细胞，用2.5%透射电镜液戊二醛在4 ℃固定过夜，PBS洗涤3次，每次10 min，1%锇酸固定，用丙酮50%、70%、80%、90%、100%脱水循环2次。包埋后电镜切片机切片，使用醋酸双氧铀浸泡30 min后ddH2O洗涤3次。柠檬酸铅浸泡10 min后ddH2O洗涤3次，透射电镜观察，并拍照记录。
1.10　Seahorse细胞代谢分析仪检测氧耗率（oxygen consumption rate，OCR）、细胞外酸化率（extracellular acidification rate，ECAR）
按照 Agilent Seahorse XFp操作指示，开启并预热检测系统后，接种HK-2细胞至细胞培养板并放入37 ℃含CO2细胞培养箱中过夜培养，提前水化探针板，用Seahorse检测液清洗细胞，将细胞培养板放入37 ℃无CO2细胞培养箱中60 min，加入OCR、ECAR试剂盒药物到探针板加药孔中，上机运行OCR、ECAR实验，并对实验数据进行统计分析。
1.11　Masson染色
组织切片脱蜡后，依据Masson试剂盒操作指南，用Weigert 铁苏木素染色液染色5 min，酸性乙醇分化，Masson蓝化液返蓝5 min，丽春红品红染色液染色，用弱酸工作液洗1 min，磷钼酸溶液洗2 min，弱酸工作液洗1 min后放入苯胺蓝染色液中染色2 min，用配制好的弱酸工作液洗1 min，95%乙醇快速脱水，无水乙醇短暂脱水3次，二甲苯透明3次，每次2 min。接着中性树胶封片并在显微镜下观察并拍照。
1.12　HE染色
切片脱水，65 ℃下在烤箱内烘烤切片30 min，组织切片浸泡在二甲苯溶液及乙醇溶液（浓度分别为100%、95%、80%、70%）中各5 min，脱蜡，用苏木素染剂进行细胞核染色3 min，1%盐酸酒精分化3 s，伊红染色2 min。显微镜下观察染色结果，并采集图像。
1.13　统计学分析
所有实验数据使用GraphPad Prism 8.0软件进行统计分析，数据以x¯±s表示，两组间数据采用Student’s t检验，多组间数据采用单因素方差分析（One-ANOVA），P<0.05表示差异具有统计学意义。
2　结果
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2.1　肾纤维化模型的建立与验证
运用单侧输尿管结扎术建立小鼠的肾纤维化模型，并在术后14 d时，麻醉小鼠并处死。经过造模的肾脏形态和对照组相比：肾皮质明显变薄、肾积水显著（图1A），并表现为肾小管萎缩、管腔扩大以及肾小管间质明显破坏（图1B）。通过免疫组织化学或免疫荧光检测纤维化标志物发现，α-SMA和FN蓄积（图1C），Masson染色提示肾脏纤维化显著升高（图1D）。Western blot检测显示纤维化标志物α-SMA和FN蛋白表达量显著升高（P<0.001，图1E），这表明肾纤维化模型建立成功。此外，还对HK-2细胞孵育TGF-β1以诱导纤维化，纤维化标志物的显著上调表明体外模拟纤维化建立成功（P<0.001，图1F）。
2.2　肾纤维化中OGDHL的表达显著下降
RT-qPCR分析发现，OGDHL的转录水平在TGF-β1诱导的纤维化HK-2细胞中降低82.9%（P<0.001，图2A）。Western blot分析表明OGDHL的蛋白水平也被明显抑制，下降81.9%（P<0.001，图2B）。同时，细胞免疫荧光染色实验证实OGDHL主要在细胞质中表达（图2C），且TGF-β1处理后OGDHL表达显著降低。在小鼠肾纤维化模型中，OGDHL的转录和翻译水平和体外模型保持一致（P<0.001，图2D、E）；为了探究OGDHL的分布，进一步通过免疫荧光染色实验分析UUO和对照组的肾脏标本，发现OGDHL主要定位于肾小管上皮细胞中（图2F），且UUO术后OGDHL的荧光强度显著降低。
2.3　肾纤维化中线粒体代谢障碍
考虑到在肾纤维化模型中大量的肾小管萎缩，而肾小管上皮细胞是维持肾功能的最主要细胞，进一步分析肾小管上皮细胞的能量代谢水平。在TGF-β1孵育的HK-2细胞中：脂肪酸氧化关键基因过氧化物酶体增殖物激活受体α（peroxisome proliferator-activated receptor α，PPAR α）、肉碱棕榈酰转移1a（carnitine palmitoyltrans-ferase 1a，CPT1a）、肉碱棕榈酰转移酶2（carnitine palmitoyltransferase 2，CPT2）、过氧化物酶酰基辅酶A氧化酶1（acyl-coenzyme A oxidase 1，ACOX1）的mRNA水平下降50.2%（P<0.05），而糖酵解相关基因己糖激酶1（hexokinase 1，HK1）、己糖激酶2（hexokinase 2，HK2）、磷酸果糖激酶血小板（phospho-fructokinase platelets，PFKP）、丙酮酸激酶M（pyruvate kinase M，PKM）上升为对照组的2.5倍（P<0.05），且ATP生成减少（0.970±0.151） µmol/L（P<0.01），提示在纤维化肾小管上皮细胞中有氧氧化被抑制而无氧氧化被激活（P<0.05，图3A~C）。由于线粒体是能量代谢的主要细胞器，进一步通过透射电镜观察线粒体的形态发现：在纤维化细胞中，线粒体肿胀变大，线粒体嵴被破坏（图3D）。这说明在纤维化肾组织中，线粒体结构被严重破坏。利用Seahorse细胞代谢仪分析检测HK-2细胞的OCR、ECAR及最大呼吸能力，结果提示，TGF-β1孵育的HK-2细胞纤维化之后，OCR下降、ECAR上升，且最大呼吸能力下降（25.260±1.920） pmol/min（P<0.001，图3E~G）。以上结果提示在肾纤维化过程中，线粒体代谢被严重破坏。
2.4　过表达OGDHL缓解纤维化肾组织中线粒体代谢障碍
OGDHL是线粒体OGDHC的限速成分之一，在线粒体代谢中起关键作用。为进一步探究OGDHL和肾纤维化过程中线粒体代谢的关系，在HK-2细胞中转染OGDHL过表达质粒并通过RT-qPCR和Western blot验证了过表达效果（P<0.001，图4A、B）。OGDHL过表达促进了纤维化状态下ATP的生成，ATP的生成增加（0.980±0.090）µmol/L（P<0.001，图4C）。同时通过检测脂肪酸氧化、糖酵解关键基因发现，OGDHL过表达缓解了TGF-β1孵育的HK-2细胞的线粒体代谢障碍（P<0.05，图4D、E）。此时线粒体的形态也显著恢复（图4F），且纤维化指标表达降低（P<0.001，图4G）。OCR、ECAR及最大呼吸能力检测结果提示，与TGF-β1组比较，OGDHL过表达后OCR上升、ECAR下降，且最大呼吸能力上升 （图4H~J） ，线粒体代谢显著恢复。以上结果提示，在肾小管上皮细胞中过表达OGDHL通过缓解线粒体代谢障碍减轻肾纤维化。
3　讨论
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本研究发现，在肾纤维化过程中肾小管上皮细胞线粒体的结构被破坏、脂肪酸氧化被抑制而糖酵解被激活，且ATP生成量显著减少，OCR下降，ECAR明显上升，线粒体呼吸能力下降，最终导致线粒体代谢重编程。体内外实验结果显示，UUO及TGF-β1诱导肾纤维化后，肾小管上皮细胞中OGDHL表达显著降低，而在体外细胞中过表达OGDHL显著缓解了TGF-β1诱导的HK-2细胞线粒体代谢障碍，细胞脂肪酸氧化恢复，糖酵解缓解，提示过表达OGDHL通过调节线粒体代谢重编程阻遏肾纤维化进程。
OGDHL是α-酮戊二酸脱氢酶复合体发挥功能的成分之一，定位于线粒体基质中，且可以催化α-酮戊二酸转化为琥珀酰辅酶A，同时产生NADH并释放二氧化碳［14-15］。该步骤是三羧酸循环中不可逆且限速的步骤，高度特异性的OGDHC抑制剂对OGDHC的抑制会导致细胞的死亡［16］。因此，作为该复合体的关键限速亚基，OGDHL表达水平的变化可能在维持线粒体代谢中发挥重要作用。
前期有研究表明，OGDHL的下调会抑制OGDHC活性，导致α-酮戊二酸积累，逆转三羧酸循环中异柠檬酸脱氢酶的氧化脱羧，最终导致柠檬酸积累和脂质合成［17］；但是也有研究发现OGDHL下调会导致脂肪酸合酶降低，导致脂肪酸合成减少［18］。这些研究充分证明了OGDHL在不同病理状态下的广泛作用潜能。而近期有研究表明，在慢性肾脏病患者中，将OGDHL特异性的递送到心脏中能改善心脏功能和心肌细胞能量状态，并显著恢复了肾功能［19］。这些证据提示OGDHL可能与细胞能量代谢状态密切相关，线粒体作为能量代谢的中心，目前尚缺乏研究报道OGDHL在肾纤维化中线粒体代谢重编程中的作用。
肾纤维化是许多慢性肾脏病的最终结果，目前临床上可用的策略只能改善或延缓慢性肾脏病的进展，但不能逆转纤维化。深入探究肾纤维化的内在机制对寻找潜在的治疗靶点至关重要［20］。啮齿动物中的实验性单侧输尿管梗阻常用于模拟人类慢性阻塞性肾病导致的肾纤维化［4，21］。前期的研究表明，失血性休克时血管平滑肌细胞线粒体能量代谢异常［22］，相同的缺血缺氧条件也发生在UUO术后的早期，肾小管上皮细胞经历代谢重编程，线粒体脂肪酸β氧化受损，糖酵解激活，进而触发脂质沉积、氧化应激以及线粒体质量减少，维持线粒体功能可以延缓纤维化进程和肾功能丧失［23］。本研究发现，在UUO诱导的肾纤维化动物模型以及TGF-β1诱导的细胞纤维化中，肾小管上皮细胞线粒体结构被破坏，发生能量代谢重编程，肾纤维化中OGDHL的表达显著下降，提示线粒体代谢重编程可能和OGDHL的缺乏相关。过表达OGDHL后发现ATP生成量显著增加，细胞能量代谢检测发现线粒体代谢显著恢复，过表达OGDHL显著缓解了纤维化。
综上所述，本研究证实了OGDHL在肾纤维化过程中的保护作用，并证实OGDHL通过促进线粒体ATP的生成缓解肾小管上皮细胞中的线粒体代谢障碍从而缓解肾纤维化，为慢性肾脏病患者的肾纤维化治疗提供了新的靶点，随着对OGDHL功能的进一步理解，未来可能为肾纤维化的治疗开辟新的方向，为临床提供新的治疗选择。

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2025年第47卷第11期
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doi: 10.16016/j.2097-0927.202501053
  • 接收时间：2025-02-02
  • 首发时间：2026-10-28
  • 出版时间：2025-06-15
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  • 收稿日期：2025-02-02
  • 修回日期：2025-04-08
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    1陆军军医大学（第三军医大学）第二附属医院肾内科，重庆市肾脏病防治重点实验室，重庆市肾病与泌尿系统疾病临床医学研究中心，重庆

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