Cardiac-specific renalase overexpression alleviates CKD-induced pathological cardiac remodeling in mice
IntroductionCKD-induced pathological cardiac remodeling is characterized by myocardial hypertrophy and cardiac fibrosis. The available therapeutic options are limited, it is thus urgently needed to identify novel therapeutic targets. Renalase (RNLS) is a newly discovered protein secreted by the kidn...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2022.1061146/full |
| _version_ | 1811177794771615744 |
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| author | Yi Wang Linnan Bai Jiejun Wen Fangfei Zhang Sijie Gu Feng Wang Jianyong Yin Niansong Wang |
| author_facet | Yi Wang Linnan Bai Jiejun Wen Fangfei Zhang Sijie Gu Feng Wang Jianyong Yin Niansong Wang |
| author_sort | Yi Wang |
| collection | DOAJ |
| description | IntroductionCKD-induced pathological cardiac remodeling is characterized by myocardial hypertrophy and cardiac fibrosis. The available therapeutic options are limited, it is thus urgently needed to identify novel therapeutic targets. Renalase (RNLS) is a newly discovered protein secreted by the kidney and was found beneficial in many renal diseases. But whether it exerts protective effects on cardiac remodeling in CKD remains unclear.MethodsRNLS knockout (KO) and wild-type (WT) mice were both used to build CKD models and the adeno-associated virus (AAV9) system was used to overexpress RNLS cardiac specifically. Echocardiography was performed to detect cardiac structural changes every 6 weeks until 18 weeks post-surgery. High throughput sequencing was performed to understand the underlying mechanisms and the effects of RNLS on cardiac fibroblasts were validated in vitro.ResultsKnockout of RNLS aggravated cardiac remodeling in CKD, while RNLS cardiac-specific overexpression significantly reduced left ventricular hypertrophy and cardiac fibrosis induced by CKD. The following RNA-sequencing analysis revealed that RNLS significantly downregulated the extracellular matrix (ECM) receptor interaction pathway, ECM organization, and several ECM-related proteins. GSEA results showed RNLS significantly downregulated several profibrotic biological processes of cardiac fibroblasts which were upregulated by CKD, including fibroblast proliferation, leukocyte migration, antigen presentation, cytokine production, and epithelial-mesenchymal transition (EMT). In vitro, we validated that RNLS reduced the primary cardiac fibroblast proliferation and α-SMA expression stimulated by TGF-β.ConclusionIn this study, we examined the cardioprotective role of RNLS in CKD-induced cardiac remodeling. RNLS may be a potential therapeutic factor that exerts an anti-fibrotic effect in pathological cardiac remodeling. |
| first_indexed | 2024-04-11T06:07:14Z |
| format | Article |
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| issn | 2297-055X |
| language | English |
| last_indexed | 2024-04-11T06:07:14Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-1d4af785d1474018a00bfa13f68582002022-12-22T04:41:27ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2022-12-01910.3389/fcvm.2022.10611461061146Cardiac-specific renalase overexpression alleviates CKD-induced pathological cardiac remodeling in miceYi Wang0Linnan Bai1Jiejun Wen2Fangfei Zhang3Sijie Gu4Feng Wang5Jianyong Yin6Niansong Wang7Department of Nephrology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Nephrology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Nephrology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaIntroductionCKD-induced pathological cardiac remodeling is characterized by myocardial hypertrophy and cardiac fibrosis. The available therapeutic options are limited, it is thus urgently needed to identify novel therapeutic targets. Renalase (RNLS) is a newly discovered protein secreted by the kidney and was found beneficial in many renal diseases. But whether it exerts protective effects on cardiac remodeling in CKD remains unclear.MethodsRNLS knockout (KO) and wild-type (WT) mice were both used to build CKD models and the adeno-associated virus (AAV9) system was used to overexpress RNLS cardiac specifically. Echocardiography was performed to detect cardiac structural changes every 6 weeks until 18 weeks post-surgery. High throughput sequencing was performed to understand the underlying mechanisms and the effects of RNLS on cardiac fibroblasts were validated in vitro.ResultsKnockout of RNLS aggravated cardiac remodeling in CKD, while RNLS cardiac-specific overexpression significantly reduced left ventricular hypertrophy and cardiac fibrosis induced by CKD. The following RNA-sequencing analysis revealed that RNLS significantly downregulated the extracellular matrix (ECM) receptor interaction pathway, ECM organization, and several ECM-related proteins. GSEA results showed RNLS significantly downregulated several profibrotic biological processes of cardiac fibroblasts which were upregulated by CKD, including fibroblast proliferation, leukocyte migration, antigen presentation, cytokine production, and epithelial-mesenchymal transition (EMT). In vitro, we validated that RNLS reduced the primary cardiac fibroblast proliferation and α-SMA expression stimulated by TGF-β.ConclusionIn this study, we examined the cardioprotective role of RNLS in CKD-induced cardiac remodeling. RNLS may be a potential therapeutic factor that exerts an anti-fibrotic effect in pathological cardiac remodeling.https://www.frontiersin.org/articles/10.3389/fcvm.2022.1061146/fullrenalasepathological cardiac remodelingCKDcardiac fibrosiscardiac fibroblasts |
| spellingShingle | Yi Wang Linnan Bai Jiejun Wen Fangfei Zhang Sijie Gu Feng Wang Jianyong Yin Niansong Wang Cardiac-specific renalase overexpression alleviates CKD-induced pathological cardiac remodeling in mice Frontiers in Cardiovascular Medicine renalase pathological cardiac remodeling CKD cardiac fibrosis cardiac fibroblasts |
| title | Cardiac-specific renalase overexpression alleviates CKD-induced pathological cardiac remodeling in mice |
| title_full | Cardiac-specific renalase overexpression alleviates CKD-induced pathological cardiac remodeling in mice |
| title_fullStr | Cardiac-specific renalase overexpression alleviates CKD-induced pathological cardiac remodeling in mice |
| title_full_unstemmed | Cardiac-specific renalase overexpression alleviates CKD-induced pathological cardiac remodeling in mice |
| title_short | Cardiac-specific renalase overexpression alleviates CKD-induced pathological cardiac remodeling in mice |
| title_sort | cardiac specific renalase overexpression alleviates ckd induced pathological cardiac remodeling in mice |
| topic | renalase pathological cardiac remodeling CKD cardiac fibrosis cardiac fibroblasts |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2022.1061146/full |
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