Daqian Gu, Meixian Chen, Yuhui Yang, Chen Lu, Chao Li, Yi Lin
{"title":"靶向PHD2/HIF-1α/HO-1通路：曲美他嗪在高血压肾病中的关键作用","authors":"Daqian Gu, Meixian Chen, Yuhui Yang, Chen Lu, Chao Li, Yi Lin","doi":"10.1080/10641963.2025.2563033","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>This study seeks to unravel the effects of trimetazidine (TMZ) on hypertensive nephropathy (HN) in mice and its underlying mechanisms.</p><p><strong>Methods: </strong>Sixty male 129 mice (8-10 weeks old) were randomly categorized into six groups (<i>n</i> = 10 per group): control, model, TMZ, TMZ + small interfering RNA targeting prolyl hydroxylase domain protein 2 (si-PHD2), TMZ + zinc protoporphyrin [ZnPP, a heme oxygenase-1 (HO-1) inhibitor], and TMZ + KC7F2 [a hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor]. All groups except the control group received angiotensin II to induce HN models. TMZ was administered by gavage for 28 days, while the other TMZ-based groups received additional si-PHD2, ZnPP, or KC7F2. Blood pressure, renal function, proinflammatory cytokines, and kidney pathology were measured. Protein/mRNA levels of PHD2, HO-1, HIF-1α, and Collagen I were analyzed via reverse transcription quantitative polymerase chain reaction/Western blot.</p><p><strong>Results: </strong>The model group showed increased blood pressure, renal injury, fibrosis, and elevated levels of PHD2, HIF-1α, HO-1, Collagen I, and inflammatory markers compared to the control group (<i>P</i> < 0.05). TMZ treatment alleviated renal damage and downregulated PHD2, while upregulating HIF-1α and HO-1. These effects were further enhanced by PHD2 knockdown (TMZ + si-PHD2), but reversed by the inhibition of HO-1 or HIF-1α (TMZ + ZnPP, TMZ + KC7F2).</p><p><strong>Conclusion: </strong>TMZ improves HN in mice by modulating the PHD2/HIF-1α/HO-1 pathway.</p>","PeriodicalId":10333,"journal":{"name":"Clinical and Experimental Hypertension","volume":"47 1","pages":"2563033"},"PeriodicalIF":3.5000,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting the PHD2/HIF-1α/HO-1 pathway: A key role of trimetazidine in hypertensive nephropathy.\",\"authors\":\"Daqian Gu, Meixian Chen, Yuhui Yang, Chen Lu, Chao Li, Yi Lin\",\"doi\":\"10.1080/10641963.2025.2563033\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>This study seeks to unravel the effects of trimetazidine (TMZ) on hypertensive nephropathy (HN) in mice and its underlying mechanisms.</p><p><strong>Methods: </strong>Sixty male 129 mice (8-10 weeks old) were randomly categorized into six groups (<i>n</i> = 10 per group): control, model, TMZ, TMZ + small interfering RNA targeting prolyl hydroxylase domain protein 2 (si-PHD2), TMZ + zinc protoporphyrin [ZnPP, a heme oxygenase-1 (HO-1) inhibitor], and TMZ + KC7F2 [a hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor]. All groups except the control group received angiotensin II to induce HN models. TMZ was administered by gavage for 28 days, while the other TMZ-based groups received additional si-PHD2, ZnPP, or KC7F2. Blood pressure, renal function, proinflammatory cytokines, and kidney pathology were measured. Protein/mRNA levels of PHD2, HO-1, HIF-1α, and Collagen I were analyzed via reverse transcription quantitative polymerase chain reaction/Western blot.</p><p><strong>Results: </strong>The model group showed increased blood pressure, renal injury, fibrosis, and elevated levels of PHD2, HIF-1α, HO-1, Collagen I, and inflammatory markers compared to the control group (<i>P</i> < 0.05). TMZ treatment alleviated renal damage and downregulated PHD2, while upregulating HIF-1α and HO-1. These effects were further enhanced by PHD2 knockdown (TMZ + si-PHD2), but reversed by the inhibition of HO-1 or HIF-1α (TMZ + ZnPP, TMZ + KC7F2).</p><p><strong>Conclusion: </strong>TMZ improves HN in mice by modulating the PHD2/HIF-1α/HO-1 pathway.</p>\",\"PeriodicalId\":10333,\"journal\":{\"name\":\"Clinical and Experimental Hypertension\",\"volume\":\"47 1\",\"pages\":\"2563033\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-12-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical and Experimental Hypertension\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/10641963.2025.2563033\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/10/11 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"PERIPHERAL VASCULAR DISEASE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Experimental Hypertension","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/10641963.2025.2563033","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/10/11 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
Targeting the PHD2/HIF-1α/HO-1 pathway: A key role of trimetazidine in hypertensive nephropathy.
Objective: This study seeks to unravel the effects of trimetazidine (TMZ) on hypertensive nephropathy (HN) in mice and its underlying mechanisms.
Methods: Sixty male 129 mice (8-10 weeks old) were randomly categorized into six groups (n = 10 per group): control, model, TMZ, TMZ + small interfering RNA targeting prolyl hydroxylase domain protein 2 (si-PHD2), TMZ + zinc protoporphyrin [ZnPP, a heme oxygenase-1 (HO-1) inhibitor], and TMZ + KC7F2 [a hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor]. All groups except the control group received angiotensin II to induce HN models. TMZ was administered by gavage for 28 days, while the other TMZ-based groups received additional si-PHD2, ZnPP, or KC7F2. Blood pressure, renal function, proinflammatory cytokines, and kidney pathology were measured. Protein/mRNA levels of PHD2, HO-1, HIF-1α, and Collagen I were analyzed via reverse transcription quantitative polymerase chain reaction/Western blot.
Results: The model group showed increased blood pressure, renal injury, fibrosis, and elevated levels of PHD2, HIF-1α, HO-1, Collagen I, and inflammatory markers compared to the control group (P < 0.05). TMZ treatment alleviated renal damage and downregulated PHD2, while upregulating HIF-1α and HO-1. These effects were further enhanced by PHD2 knockdown (TMZ + si-PHD2), but reversed by the inhibition of HO-1 or HIF-1α (TMZ + ZnPP, TMZ + KC7F2).
Conclusion: TMZ improves HN in mice by modulating the PHD2/HIF-1α/HO-1 pathway.
期刊介绍：
Clinical and Experimental Hypertension is a reputable journal that has converted to a full Open Access format starting from Volume 45 in 2023. While previous volumes are still accessible through a Pay to Read model, the journal now provides free and open access to its content. It serves as an international platform for the exchange of up-to-date scientific and clinical information concerning both human and animal hypertension. The journal publishes a wide range of articles, including full research papers, solicited and unsolicited reviews, and commentaries. Through these publications, the journal aims to enhance current understanding and support the timely detection, management, control, and prevention of hypertension-related conditions.
One notable aspect of Clinical and Experimental Hypertension is its coverage of special issues that focus on the proceedings of symposia dedicated to hypertension research. This feature allows researchers and clinicians to delve deeper into the latest advancements in this field.
The journal is abstracted and indexed in several renowned databases, including Pharmacoeconomics and Outcomes News (Online), Reactions Weekly (Online), CABI, EBSCOhost, Elsevier BV, International Atomic Energy Agency, and the National Library of Medicine, among others. These affiliations ensure that the journal's content receives broad visibility and facilitates its discoverability by professionals and researchers in related disciplines.
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