Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial Fission
Yingxue Sun,1,* Shi Jin,1,* Jun Chen,2,* Jian Zhang,1 Yufei Lu,1 Qiuyu Gu,1 Zhixin Yan,1 Weize Chen,1 Annan Chen,1 Yi Fang,1 Wenye Geng,3 Xialian Xu,1 Nana Song1 1Department of Nephrology, Zhongshan Hospital, Fudan University; Shanghai Medical Center of Kidney; Shanghai Insti...
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Dove Medical Press
2025-02-01
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| author | Sun Y Jin S Chen J Zhang J Lu Y Gu Q Yan Z Chen W Chen A Fang Y Geng W Xu X Song N |
| author_facet | Sun Y Jin S Chen J Zhang J Lu Y Gu Q Yan Z Chen W Chen A Fang Y Geng W Xu X Song N |
| author_sort | Sun Y |
| collection | DOAJ |
| description | Yingxue Sun,1,* Shi Jin,1,* Jun Chen,2,* Jian Zhang,1 Yufei Lu,1 Qiuyu Gu,1 Zhixin Yan,1 Weize Chen,1 Annan Chen,1 Yi Fang,1 Wenye Geng,3 Xialian Xu,1 Nana Song1 1Department of Nephrology, Zhongshan Hospital, Fudan University; Shanghai Medical Center of Kidney; Shanghai Institute of Kidney and Dialysis; Shanghai Key Laboratory of Kidney and Blood Purification; Hemodialysis Quality Control Center of Shanghai, Shanghai, 200032, People’s Republic of China; 2Department of Pathology, Changzheng Hospital, Naval Military Medical University, Shanghai, 200003, People’s Republic of China; 3Scientific Research Department of Shanghai Medical College, Fudan Zhangjiang Institute, Fudan University, Shanghai, 201203, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xialian Xu; Nana Song, Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China, Tel +86-021-64041990-2138, Fax +86-021-64038038, Email xu.xialian@zs-hospital.sh.cn; song.nana@zs-hospital.sh.cnObjective: This study aimed to investigate the mechanisms and specific targets of cordycepin in the treatment of renal fibrosis using a unilateral ischemia-reperfusion (UIR) model.Methods: A UIR mouse model was established, followed by intraperitoneal injections of cordycepin and Mdivi-1. Masson’s trichrome staining and PAS staining were used to identify renal tubulointerstitial fibrosis and assess the degree of renal injury. Fibrosis markers and mitochondrial dynamics-related proteins were evaluated using Western blotting, while differential gene expression and pathway enrichment were analyzed by RNA-seq. Molecular docking, molecular dynamics simulations and surface plasmon resonance were conducted to validate the specific binding sites of cordycepin on the target protein Drp1. Immunofluorescence and in vitro experiments further elucidated the therapeutic mechanism of cordycepin.Results: In vivo experiments showed that intraperitoneal injection of cordycepin significantly reduced renal inflammation and fibrosis, lowered serum creatinine levels, and decreased collagen deposition. Transcriptome analysis revealed that cordycepin treatment downregulated the mitochondrial fission pathway and upregulated the mitochondrial fusion pathway. Western blotting showed reduced levels of fibrosis markers α-SMA and FN, as well as downregulation of Drp1, MFF, and Fis1, and upregulation of OPA1 and Mfn2. In vitro, cordycepin inhibited TGF-β-induced injury in NRK-52E cells, reducing Drp1 expression and IL-6 secretion. Crosstalk experiments confirmed that decreased IL-6 levels were crucial for cordycepin anti-fibrotic effects by suppressing fibroblast activation.Conclusion: Cordycepin ameliorates renal fibrosis by targeting Drp1 to inhibit mitochondrial fission in injured renal tubular epithelial cells, reducing IL-6 secretion and inhibiting fibroblast activation.Keywords: cordycepin, Drp1, renal fibrosis, mitochondrial fission, UIR, IL-6 |
| format | Article |
| id | doaj-art-13fe334ffa674ec2a99089baa2824eab |
| institution | DOAJ |
| issn | 1177-8881 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj-art-13fe334ffa674ec2a99089baa2824eab2025-08-20T03:12:04ZengDove Medical PressDrug Design, Development and Therapy1177-88812025-02-01Volume 1912711287100481Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial FissionSun YJin SChen JZhang JLu YGu QYan ZChen WChen AFang YGeng WXu XSong NYingxue Sun,1,* Shi Jin,1,* Jun Chen,2,* Jian Zhang,1 Yufei Lu,1 Qiuyu Gu,1 Zhixin Yan,1 Weize Chen,1 Annan Chen,1 Yi Fang,1 Wenye Geng,3 Xialian Xu,1 Nana Song1 1Department of Nephrology, Zhongshan Hospital, Fudan University; Shanghai Medical Center of Kidney; Shanghai Institute of Kidney and Dialysis; Shanghai Key Laboratory of Kidney and Blood Purification; Hemodialysis Quality Control Center of Shanghai, Shanghai, 200032, People’s Republic of China; 2Department of Pathology, Changzheng Hospital, Naval Military Medical University, Shanghai, 200003, People’s Republic of China; 3Scientific Research Department of Shanghai Medical College, Fudan Zhangjiang Institute, Fudan University, Shanghai, 201203, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xialian Xu; Nana Song, Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China, Tel +86-021-64041990-2138, Fax +86-021-64038038, Email xu.xialian@zs-hospital.sh.cn; song.nana@zs-hospital.sh.cnObjective: This study aimed to investigate the mechanisms and specific targets of cordycepin in the treatment of renal fibrosis using a unilateral ischemia-reperfusion (UIR) model.Methods: A UIR mouse model was established, followed by intraperitoneal injections of cordycepin and Mdivi-1. Masson’s trichrome staining and PAS staining were used to identify renal tubulointerstitial fibrosis and assess the degree of renal injury. Fibrosis markers and mitochondrial dynamics-related proteins were evaluated using Western blotting, while differential gene expression and pathway enrichment were analyzed by RNA-seq. Molecular docking, molecular dynamics simulations and surface plasmon resonance were conducted to validate the specific binding sites of cordycepin on the target protein Drp1. Immunofluorescence and in vitro experiments further elucidated the therapeutic mechanism of cordycepin.Results: In vivo experiments showed that intraperitoneal injection of cordycepin significantly reduced renal inflammation and fibrosis, lowered serum creatinine levels, and decreased collagen deposition. Transcriptome analysis revealed that cordycepin treatment downregulated the mitochondrial fission pathway and upregulated the mitochondrial fusion pathway. Western blotting showed reduced levels of fibrosis markers α-SMA and FN, as well as downregulation of Drp1, MFF, and Fis1, and upregulation of OPA1 and Mfn2. In vitro, cordycepin inhibited TGF-β-induced injury in NRK-52E cells, reducing Drp1 expression and IL-6 secretion. Crosstalk experiments confirmed that decreased IL-6 levels were crucial for cordycepin anti-fibrotic effects by suppressing fibroblast activation.Conclusion: Cordycepin ameliorates renal fibrosis by targeting Drp1 to inhibit mitochondrial fission in injured renal tubular epithelial cells, reducing IL-6 secretion and inhibiting fibroblast activation.Keywords: cordycepin, Drp1, renal fibrosis, mitochondrial fission, UIR, IL-6https://www.dovepress.com/cordycepin-ameliorates-renal-interstitial-fibrosis-by-inhibiting-drp1--peer-reviewed-fulltext-article-DDDTcordycepindrp1renal fibrosismitochondrial fissionuiril-6 |
| spellingShingle | Sun Y Jin S Chen J Zhang J Lu Y Gu Q Yan Z Chen W Chen A Fang Y Geng W Xu X Song N Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial Fission Drug Design, Development and Therapy cordycepin drp1 renal fibrosis mitochondrial fission uir il-6 |
| title | Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial Fission |
| title_full | Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial Fission |
| title_fullStr | Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial Fission |
| title_full_unstemmed | Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial Fission |
| title_short | Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial Fission |
| title_sort | cordycepin ameliorates renal interstitial fibrosis by inhibiting drp1 mediated mitochondrial fission |
| topic | cordycepin drp1 renal fibrosis mitochondrial fission uir il-6 |
| url | https://www.dovepress.com/cordycepin-ameliorates-renal-interstitial-fibrosis-by-inhibiting-drp1--peer-reviewed-fulltext-article-DDDT |
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