Linagliptin Protects against Endotoxin-Induced Acute Kidney Injury in Rats by Decreasing Inflammatory Cytokines and Reactive Oxygen Species
Septic shock can increase pro-inflammatory cytokines, reactive oxygen species (ROS), and multiple organ dysfunction syndrome (MODs) and even lead to death. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been proven to exert potential antioxidant and anti-inflammatory effects. We investigated the eff...
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/20/11190 |
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| author | Tsung-Jui Wu Yi-Jen Hsieh Chia-Wen Lu Chung-Jen Lee Bang-Gee Hsu |
| author_facet | Tsung-Jui Wu Yi-Jen Hsieh Chia-Wen Lu Chung-Jen Lee Bang-Gee Hsu |
| author_sort | Tsung-Jui Wu |
| collection | DOAJ |
| description | Septic shock can increase pro-inflammatory cytokines, reactive oxygen species (ROS), and multiple organ dysfunction syndrome (MODs) and even lead to death. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been proven to exert potential antioxidant and anti-inflammatory effects. We investigated the effects of linagliptin on endotoxic shock and acute kidney injury (AKI) in animal and cell models. In the cell model, linagliptin attenuated ROS by activating the AMP-activated protein kinase (AMPK) pathway, restoring nuclear-factor-erythroid-2-related factor (Nrf2) and heme oxygenase 1 (HO-1) protein, and decreasing pro-inflammatory cytokines (tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β)). In the animal model, 14-week-old conscious Wistar–Kyoto rats were randomly divided into three groups (<i>n</i> = 8 in each group). Endotoxin shock with MODs was induced by the intravenous injection of Klebsiella pneumoniae lipopolysaccharide (LPS, 20 mg/kg). Linagliptin improved animal survival without affecting hemodynamic profiles. In the histopathology and immunohistochemistry examinations of the rat kidneys, linagliptin (10 mg/kg) suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inducible nitric oxide synthase (iNOS), decreased injury scores, and preserved E-cadherin expression from LPS damage. In conclusion, linagliptin ameliorated endotoxin-shock-induced AKI by reducing ROS via AMPK pathway activation and suppressing the release of TNF-α and IL-1β in conscious rats. |
| first_indexed | 2024-03-10T06:30:03Z |
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| language | English |
| last_indexed | 2024-03-10T06:30:03Z |
| publishDate | 2021-10-01 |
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| spelling | doaj.art-b63ff1cdd550476ca30b48373169c02e2023-11-22T18:35:21ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122201119010.3390/ijms222011190Linagliptin Protects against Endotoxin-Induced Acute Kidney Injury in Rats by Decreasing Inflammatory Cytokines and Reactive Oxygen SpeciesTsung-Jui Wu0Yi-Jen Hsieh1Chia-Wen Lu2Chung-Jen Lee3Bang-Gee Hsu4Division of Nephrology, Department of Medicine, Hualien Armed Forces General Hospital, Hualien 97144, TaiwanDivision of Nephrology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97002, TaiwanInstitute of Medical Sciences, Tzu Chi University, Hualien 97004, TaiwanDepartment of Nursing, Tzu Chi University of Science and Technology, Hualien 97005, TaiwanInstitute of Medical Sciences, Tzu Chi University, Hualien 97004, TaiwanSeptic shock can increase pro-inflammatory cytokines, reactive oxygen species (ROS), and multiple organ dysfunction syndrome (MODs) and even lead to death. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been proven to exert potential antioxidant and anti-inflammatory effects. We investigated the effects of linagliptin on endotoxic shock and acute kidney injury (AKI) in animal and cell models. In the cell model, linagliptin attenuated ROS by activating the AMP-activated protein kinase (AMPK) pathway, restoring nuclear-factor-erythroid-2-related factor (Nrf2) and heme oxygenase 1 (HO-1) protein, and decreasing pro-inflammatory cytokines (tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β)). In the animal model, 14-week-old conscious Wistar–Kyoto rats were randomly divided into three groups (<i>n</i> = 8 in each group). Endotoxin shock with MODs was induced by the intravenous injection of Klebsiella pneumoniae lipopolysaccharide (LPS, 20 mg/kg). Linagliptin improved animal survival without affecting hemodynamic profiles. In the histopathology and immunohistochemistry examinations of the rat kidneys, linagliptin (10 mg/kg) suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inducible nitric oxide synthase (iNOS), decreased injury scores, and preserved E-cadherin expression from LPS damage. In conclusion, linagliptin ameliorated endotoxin-shock-induced AKI by reducing ROS via AMPK pathway activation and suppressing the release of TNF-α and IL-1β in conscious rats.https://www.mdpi.com/1422-0067/22/20/11190dipeptidyl peptidase-4 inhibitorslinagliptinacute kidney injuryendotoxic shockreactive oxygen speciespro-inflammatory cytokines |
| spellingShingle | Tsung-Jui Wu Yi-Jen Hsieh Chia-Wen Lu Chung-Jen Lee Bang-Gee Hsu Linagliptin Protects against Endotoxin-Induced Acute Kidney Injury in Rats by Decreasing Inflammatory Cytokines and Reactive Oxygen Species International Journal of Molecular Sciences dipeptidyl peptidase-4 inhibitors linagliptin acute kidney injury endotoxic shock reactive oxygen species pro-inflammatory cytokines |
| title | Linagliptin Protects against Endotoxin-Induced Acute Kidney Injury in Rats by Decreasing Inflammatory Cytokines and Reactive Oxygen Species |
| title_full | Linagliptin Protects against Endotoxin-Induced Acute Kidney Injury in Rats by Decreasing Inflammatory Cytokines and Reactive Oxygen Species |
| title_fullStr | Linagliptin Protects against Endotoxin-Induced Acute Kidney Injury in Rats by Decreasing Inflammatory Cytokines and Reactive Oxygen Species |
| title_full_unstemmed | Linagliptin Protects against Endotoxin-Induced Acute Kidney Injury in Rats by Decreasing Inflammatory Cytokines and Reactive Oxygen Species |
| title_short | Linagliptin Protects against Endotoxin-Induced Acute Kidney Injury in Rats by Decreasing Inflammatory Cytokines and Reactive Oxygen Species |
| title_sort | linagliptin protects against endotoxin induced acute kidney injury in rats by decreasing inflammatory cytokines and reactive oxygen species |
| topic | dipeptidyl peptidase-4 inhibitors linagliptin acute kidney injury endotoxic shock reactive oxygen species pro-inflammatory cytokines |
| url | https://www.mdpi.com/1422-0067/22/20/11190 |
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