4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling
Abstract Background Septic acute kidney injury (S-AKI) is the leading form of acute kidney failure among hospitalized patients, and the inflammatory response is involved in this process. 4-octyl itaconate (4-OI) is a multi-target itaconate derivative with potent anti-inflammatory action. However, it...
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-023-00631-8 |
| _version_ | 1797836449194704896 |
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| author | Lujun Xu Juan Cai Chenrui Li Ming Yang Tongyue Duan Qing Zhao Yiyun Xi Liya Sun Liyu He Chengyuan Tang Lin Sun |
| author_facet | Lujun Xu Juan Cai Chenrui Li Ming Yang Tongyue Duan Qing Zhao Yiyun Xi Liya Sun Liyu He Chengyuan Tang Lin Sun |
| author_sort | Lujun Xu |
| collection | DOAJ |
| description | Abstract Background Septic acute kidney injury (S-AKI) is the leading form of acute kidney failure among hospitalized patients, and the inflammatory response is involved in this process. 4-octyl itaconate (4-OI) is a multi-target itaconate derivative with potent anti-inflammatory action. However, it remains elusive whether and how 4-OI contributes to the regulation of S-AKI. Methods We employed a lipopolysaccharide (LPS)-induced AKI murine model and explored the potential renoprotective effect of 4-OI in vivo. In vitro experiments, BUMPT cells, a murine renal tubular cell line, were conducted to examine the effects of 4-OI on inflammation, oxidative stress, and mitophagy. Moreover, STAT3 plasmid was transfected in BUMPT cells to investigate the role of STAT3 signaling in the 4-OI-administrated state. Results We demonstrate that 4-OI protects against S-AKI through suppressing inflammation and oxidative stress and enhancing mitophagy. 4-OI significantly reduced the levels of Scr, BUN, Ngal as well as the tubular injury in LPS-induced AKI mice. 4-OI restrained inflammation by reducing macrophage infiltration and suppressing the expression of IL-1β and NLRP3 in the septic kidney. 4-OI also reduced ROS levels, as well as cleaved caspase-3 and boosted antioxidants such as HO-1, and NQO1 in mice. In addition, the 4-OI treatment significantly promoted mitophagy. Mechanistically, 4-OI activated Nrf2 signaling and suppressed phosphorylated STAT3 in vivo and vitro. Molecular docking revealed the binding affinity of 4-OI towards STAT3. ML385, a specific Nrf2 inhibitor, partially repressed the anti-inflammatory and anti-oxidative effects of 4-OI and partially restricted the mitophagy induced by 4-OI in vivo and in vitro. Transfected with STAT3 plasmid partially suppressed mitophagy and the anti-inflammatory effect provoked by 4-OI in vitro. Conclusion These data suggest that 4-OI ameliorates LPS-induced AKI by suppressing inflammation and oxidative stress and enhancing mitophagy through the overactivation of the Nrf2 signaling pathway, and inactivation of STAT3. Our study identifies 4-OI as a promising pharmacologic for S-AKI. |
| first_indexed | 2024-04-09T15:09:04Z |
| format | Article |
| id | doaj.art-e90c99c0434f4d3686e01b72e9770771 |
| institution | Directory Open Access Journal |
| issn | 1528-3658 |
| language | English |
| last_indexed | 2024-04-09T15:09:04Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-e90c99c0434f4d3686e01b72e97707712023-04-30T11:19:04ZengBMCMolecular Medicine1528-36582023-04-0129111510.1186/s10020-023-00631-84-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signalingLujun Xu0Juan Cai1Chenrui Li2Ming Yang3Tongyue Duan4Qing Zhao5Yiyun Xi6Liya Sun7Liyu He8Chengyuan Tang9Lin Sun10Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South UniversityDepartment of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South UniversityDepartment of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South UniversityDepartment of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South UniversityDepartment of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South UniversityDepartment of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South UniversityDepartment of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South UniversityDepartment of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South UniversityDepartment of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South UniversityDepartment of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South UniversityDepartment of Nephrology, Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South UniversityAbstract Background Septic acute kidney injury (S-AKI) is the leading form of acute kidney failure among hospitalized patients, and the inflammatory response is involved in this process. 4-octyl itaconate (4-OI) is a multi-target itaconate derivative with potent anti-inflammatory action. However, it remains elusive whether and how 4-OI contributes to the regulation of S-AKI. Methods We employed a lipopolysaccharide (LPS)-induced AKI murine model and explored the potential renoprotective effect of 4-OI in vivo. In vitro experiments, BUMPT cells, a murine renal tubular cell line, were conducted to examine the effects of 4-OI on inflammation, oxidative stress, and mitophagy. Moreover, STAT3 plasmid was transfected in BUMPT cells to investigate the role of STAT3 signaling in the 4-OI-administrated state. Results We demonstrate that 4-OI protects against S-AKI through suppressing inflammation and oxidative stress and enhancing mitophagy. 4-OI significantly reduced the levels of Scr, BUN, Ngal as well as the tubular injury in LPS-induced AKI mice. 4-OI restrained inflammation by reducing macrophage infiltration and suppressing the expression of IL-1β and NLRP3 in the septic kidney. 4-OI also reduced ROS levels, as well as cleaved caspase-3 and boosted antioxidants such as HO-1, and NQO1 in mice. In addition, the 4-OI treatment significantly promoted mitophagy. Mechanistically, 4-OI activated Nrf2 signaling and suppressed phosphorylated STAT3 in vivo and vitro. Molecular docking revealed the binding affinity of 4-OI towards STAT3. ML385, a specific Nrf2 inhibitor, partially repressed the anti-inflammatory and anti-oxidative effects of 4-OI and partially restricted the mitophagy induced by 4-OI in vivo and in vitro. Transfected with STAT3 plasmid partially suppressed mitophagy and the anti-inflammatory effect provoked by 4-OI in vitro. Conclusion These data suggest that 4-OI ameliorates LPS-induced AKI by suppressing inflammation and oxidative stress and enhancing mitophagy through the overactivation of the Nrf2 signaling pathway, and inactivation of STAT3. Our study identifies 4-OI as a promising pharmacologic for S-AKI.https://doi.org/10.1186/s10020-023-00631-8sepsisAcute kidney injury4-octyl itaconateOxidative stressInflammationMitophagy |
| spellingShingle | Lujun Xu Juan Cai Chenrui Li Ming Yang Tongyue Duan Qing Zhao Yiyun Xi Liya Sun Liyu He Chengyuan Tang Lin Sun 4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling Molecular Medicine sepsis Acute kidney injury 4-octyl itaconate Oxidative stress Inflammation Mitophagy |
| title | 4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling |
| title_full | 4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling |
| title_fullStr | 4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling |
| title_full_unstemmed | 4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling |
| title_short | 4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling |
| title_sort | 4 octyl itaconate attenuates lps induced acute kidney injury by activating nrf2 and inhibiting stat3 signaling |
| topic | sepsis Acute kidney injury 4-octyl itaconate Oxidative stress Inflammation Mitophagy |
| url | https://doi.org/10.1186/s10020-023-00631-8 |
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