Empagliflozin improves renal ischemia–reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK–OPA1 pathway promotion
Abstract Background Renal ischemia–reperfusion injury (IRI) is one reason for renal transplantation failure. Recent studies have shown that mitochondrial dynamics is closely related to IRI, and that inhibition or reversal of mitochondrial division protects organs against IRI. Optic atrophy protein 1...
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BMC
2023-05-01
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Series: | Cellular & Molecular Biology Letters |
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Online Access: | https://doi.org/10.1186/s11658-023-00457-6 |
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author | Wenbo Yang Xiaoli Li Liujie He Shuyang Zhu Shicong Lai Xiaopeng Zhang Zixiong Huang Biyue Yu Chunping Cui Qiang Wang |
author_facet | Wenbo Yang Xiaoli Li Liujie He Shuyang Zhu Shicong Lai Xiaopeng Zhang Zixiong Huang Biyue Yu Chunping Cui Qiang Wang |
author_sort | Wenbo Yang |
collection | DOAJ |
description | Abstract Background Renal ischemia–reperfusion injury (IRI) is one reason for renal transplantation failure. Recent studies have shown that mitochondrial dynamics is closely related to IRI, and that inhibition or reversal of mitochondrial division protects organs against IRI. Optic atrophy protein 1 (OPA1), an important factor in mitochondrial fusion, has been shown to be upregulated by sodium-glucose cotransporter 2 inhibitor (SGLT2i). Also, the antiinflammatory effects of SGLT2i have been demonstrated in renal cells. Thus, we hypothesized that empagliflozin could prevent IRI through inhibiting mitochondrial division and reducing inflammation. Methods Using hematoxylin–eosin staining, enzyme linked immunosorbent assay (ELISA), flow cytometry, immunofluorescent staining, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining, real-time PCR, RNA-sequencing, and western blot, we analyzed renal tubular tissue from in vivo and in vitro experiments. Results Through animal experiments and sequencing analysis, we first confirmed the protection against IRI and the regulation of mitochondrial dynamics-related factors and inflammatory factors by empagliflozin pretreatment. Then, through hypoxia/reoxygenation (H/R) cellular experiments, we confirmed that empagliflozin could inhibit mitochondrial shortening and division and upregulate OPA1 in human renal tubular epithelial cell line (HK-2) cells. Subsequently, we knocked down OPA1, and mitochondrial division and shortening were observed, which could be alleviated by empagliflozin treatment. Combined with the previous results, we concluded that OPA1 downregulation leads to mitochondrial division and shortening, and empagliflozin can alleviate the condition by upregulating OPA1. We further explored the pathway through which empagliflozin functions. Related studies have shown the activation of AMPK pathway by empagliflozin and the close correlation between the AMPK pathway and OPA1. In our study, we blocked the AMPK pathway, and OPA1 upregulation by empagliflozin was not observed, thus demonstrating the dependence of empagliflozin on the AMPK pathway. Conclusion The results indicated that empagliflozin could prevent or alleviate renal IRI through antiinflammatory effects and the AMPK–OPA1 pathway. Ischemia–reperfusion injury is an inevitable challenge in organ transplantation. It is necessary to develop a new therapeutic strategy for IRI prevention in addition to refining the transplantation process. In this study, we confirmed the preventive and protective effects of empagliflozin in renal ischemia–reperfusion injury. Based on these findings, empagliflozin is promising to be a preventive agent for renal ischemia–reperfusion injury and can be applied for preemptive administration in kidney transplantation. |
first_indexed | 2024-03-13T10:14:01Z |
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spelling | doaj.art-dd84faf7d6114f06b94200acfeeba4c82023-05-21T11:21:24ZengBMCCellular & Molecular Biology Letters1689-13922023-05-0128111910.1186/s11658-023-00457-6Empagliflozin improves renal ischemia–reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK–OPA1 pathway promotionWenbo Yang0Xiaoli Li1Liujie He2Shuyang Zhu3Shicong Lai4Xiaopeng Zhang5Zixiong Huang6Biyue Yu7Chunping Cui8Qiang Wang9Department of Urology, Peking University People’s HospitalDepartment of the Eighth Healthcare, the Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General HospitalNaval Medical UniversityNaval Medical UniversityDepartment of Urology, Peking University People’s HospitalDepartment of Urology, Peking University People’s HospitalDepartment of Urology, Peking University People’s HospitalSchool of Life Sciences, Hebei UniversityState Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of LifeomicsDepartment of Urology, Peking University People’s HospitalAbstract Background Renal ischemia–reperfusion injury (IRI) is one reason for renal transplantation failure. Recent studies have shown that mitochondrial dynamics is closely related to IRI, and that inhibition or reversal of mitochondrial division protects organs against IRI. Optic atrophy protein 1 (OPA1), an important factor in mitochondrial fusion, has been shown to be upregulated by sodium-glucose cotransporter 2 inhibitor (SGLT2i). Also, the antiinflammatory effects of SGLT2i have been demonstrated in renal cells. Thus, we hypothesized that empagliflozin could prevent IRI through inhibiting mitochondrial division and reducing inflammation. Methods Using hematoxylin–eosin staining, enzyme linked immunosorbent assay (ELISA), flow cytometry, immunofluorescent staining, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining, real-time PCR, RNA-sequencing, and western blot, we analyzed renal tubular tissue from in vivo and in vitro experiments. Results Through animal experiments and sequencing analysis, we first confirmed the protection against IRI and the regulation of mitochondrial dynamics-related factors and inflammatory factors by empagliflozin pretreatment. Then, through hypoxia/reoxygenation (H/R) cellular experiments, we confirmed that empagliflozin could inhibit mitochondrial shortening and division and upregulate OPA1 in human renal tubular epithelial cell line (HK-2) cells. Subsequently, we knocked down OPA1, and mitochondrial division and shortening were observed, which could be alleviated by empagliflozin treatment. Combined with the previous results, we concluded that OPA1 downregulation leads to mitochondrial division and shortening, and empagliflozin can alleviate the condition by upregulating OPA1. We further explored the pathway through which empagliflozin functions. Related studies have shown the activation of AMPK pathway by empagliflozin and the close correlation between the AMPK pathway and OPA1. In our study, we blocked the AMPK pathway, and OPA1 upregulation by empagliflozin was not observed, thus demonstrating the dependence of empagliflozin on the AMPK pathway. Conclusion The results indicated that empagliflozin could prevent or alleviate renal IRI through antiinflammatory effects and the AMPK–OPA1 pathway. Ischemia–reperfusion injury is an inevitable challenge in organ transplantation. It is necessary to develop a new therapeutic strategy for IRI prevention in addition to refining the transplantation process. In this study, we confirmed the preventive and protective effects of empagliflozin in renal ischemia–reperfusion injury. Based on these findings, empagliflozin is promising to be a preventive agent for renal ischemia–reperfusion injury and can be applied for preemptive administration in kidney transplantation.https://doi.org/10.1186/s11658-023-00457-6Renal ischemia–reperfusion injuryEmpagliflozinSGLT2iInflammationMitochondrial dynamicsOPA1 |
spellingShingle | Wenbo Yang Xiaoli Li Liujie He Shuyang Zhu Shicong Lai Xiaopeng Zhang Zixiong Huang Biyue Yu Chunping Cui Qiang Wang Empagliflozin improves renal ischemia–reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK–OPA1 pathway promotion Cellular & Molecular Biology Letters Renal ischemia–reperfusion injury Empagliflozin SGLT2i Inflammation Mitochondrial dynamics OPA1 |
title | Empagliflozin improves renal ischemia–reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK–OPA1 pathway promotion |
title_full | Empagliflozin improves renal ischemia–reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK–OPA1 pathway promotion |
title_fullStr | Empagliflozin improves renal ischemia–reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK–OPA1 pathway promotion |
title_full_unstemmed | Empagliflozin improves renal ischemia–reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK–OPA1 pathway promotion |
title_short | Empagliflozin improves renal ischemia–reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK–OPA1 pathway promotion |
title_sort | empagliflozin improves renal ischemia reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through ampk opa1 pathway promotion |
topic | Renal ischemia–reperfusion injury Empagliflozin SGLT2i Inflammation Mitochondrial dynamics OPA1 |
url | https://doi.org/10.1186/s11658-023-00457-6 |
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