JP4-039 Mitigates Cisplatin-Induced Acute Kidney Injury by Inhibiting Oxidative Stress and Blocking Apoptosis and Ferroptosis in Mice
Cisplatin is a commonly used chemotherapeutic agent in the treatment of a wide array of cancers. Due to its active transport into the kidney proximal tubule cells, cisplatin treatment can cause a buildup of this nephrotoxic compound in the kidney, resulting in acute kidney injury (AKI). About 30% of...
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MDPI AG
2024-12-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/13/12/1534 |
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| author | Merlin Airik Kacian Clayton Peter Wipf Rannar Airik |
| author_facet | Merlin Airik Kacian Clayton Peter Wipf Rannar Airik |
| author_sort | Merlin Airik |
| collection | DOAJ |
| description | Cisplatin is a commonly used chemotherapeutic agent in the treatment of a wide array of cancers. Due to its active transport into the kidney proximal tubule cells, cisplatin treatment can cause a buildup of this nephrotoxic compound in the kidney, resulting in acute kidney injury (AKI). About 30% of patients receiving cisplatin chemotherapy develop cisplatin-induced AKI. JP4-039 is a mitochondria-targeted reactive oxygen species (ROS) and electron scavenger. Recent studies have shown that JP4-039 mitigates a variety of genotoxic insults in preclinical studies in rodents by suppressing oxidative stress-mediated tissue damage and blocking apoptosis and ferroptosis. However, the benefits of JP4-039 treatment have not been tested in the setting of AKI. In this study, we investigated the potential renoprotective effect of JP4-039 on cisplatin-induced AKI. To address this goal, we treated mice with JP4-039 before or after cisplatin administration and analyzed them for functional and molecular changes in the kidney. JP4-039 co-administration attenuated cisplatin-induced renal dysfunction and histopathological changes. Upregulation of tubular injury markers was also suppressed by JP4-039. Mechanistically, JP4-039 suppressed lipid peroxidation, prevented tissue oxidative stress, and preserved the glutathione levels in cisplatin-injected mice. An increase in cisplatin-induced apoptosis and ferroptosis was also alleviated by the compound. Moreover, JP4-039 inhibited cytokine overproduction in cisplatin-injected mice. Together, our findings demonstrate that JP4-039 is a promising therapeutic agent against cisplatin-induced kidney injury. |
| format | Article |
| id | doaj-art-24318ebddea646d0a37cc7a7a19fceee |
| institution | Kabale University |
| issn | 2076-3921 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-24318ebddea646d0a37cc7a7a19fceee2024-12-27T14:06:53ZengMDPI AGAntioxidants2076-39212024-12-011312153410.3390/antiox13121534JP4-039 Mitigates Cisplatin-Induced Acute Kidney Injury by Inhibiting Oxidative Stress and Blocking Apoptosis and Ferroptosis in MiceMerlin Airik0Kacian Clayton1Peter Wipf2Rannar Airik3Division of Nephrology, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USADivision of Nephrology, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USADivision of Nephrology, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USACisplatin is a commonly used chemotherapeutic agent in the treatment of a wide array of cancers. Due to its active transport into the kidney proximal tubule cells, cisplatin treatment can cause a buildup of this nephrotoxic compound in the kidney, resulting in acute kidney injury (AKI). About 30% of patients receiving cisplatin chemotherapy develop cisplatin-induced AKI. JP4-039 is a mitochondria-targeted reactive oxygen species (ROS) and electron scavenger. Recent studies have shown that JP4-039 mitigates a variety of genotoxic insults in preclinical studies in rodents by suppressing oxidative stress-mediated tissue damage and blocking apoptosis and ferroptosis. However, the benefits of JP4-039 treatment have not been tested in the setting of AKI. In this study, we investigated the potential renoprotective effect of JP4-039 on cisplatin-induced AKI. To address this goal, we treated mice with JP4-039 before or after cisplatin administration and analyzed them for functional and molecular changes in the kidney. JP4-039 co-administration attenuated cisplatin-induced renal dysfunction and histopathological changes. Upregulation of tubular injury markers was also suppressed by JP4-039. Mechanistically, JP4-039 suppressed lipid peroxidation, prevented tissue oxidative stress, and preserved the glutathione levels in cisplatin-injected mice. An increase in cisplatin-induced apoptosis and ferroptosis was also alleviated by the compound. Moreover, JP4-039 inhibited cytokine overproduction in cisplatin-injected mice. Together, our findings demonstrate that JP4-039 is a promising therapeutic agent against cisplatin-induced kidney injury.https://www.mdpi.com/2076-3921/13/12/1534acute kidney injuryoxidative stressantioxidantsJP4-039apoptosisferroptosis |
| spellingShingle | Merlin Airik Kacian Clayton Peter Wipf Rannar Airik JP4-039 Mitigates Cisplatin-Induced Acute Kidney Injury by Inhibiting Oxidative Stress and Blocking Apoptosis and Ferroptosis in Mice Antioxidants acute kidney injury oxidative stress antioxidants JP4-039 apoptosis ferroptosis |
| title | JP4-039 Mitigates Cisplatin-Induced Acute Kidney Injury by Inhibiting Oxidative Stress and Blocking Apoptosis and Ferroptosis in Mice |
| title_full | JP4-039 Mitigates Cisplatin-Induced Acute Kidney Injury by Inhibiting Oxidative Stress and Blocking Apoptosis and Ferroptosis in Mice |
| title_fullStr | JP4-039 Mitigates Cisplatin-Induced Acute Kidney Injury by Inhibiting Oxidative Stress and Blocking Apoptosis and Ferroptosis in Mice |
| title_full_unstemmed | JP4-039 Mitigates Cisplatin-Induced Acute Kidney Injury by Inhibiting Oxidative Stress and Blocking Apoptosis and Ferroptosis in Mice |
| title_short | JP4-039 Mitigates Cisplatin-Induced Acute Kidney Injury by Inhibiting Oxidative Stress and Blocking Apoptosis and Ferroptosis in Mice |
| title_sort | jp4 039 mitigates cisplatin induced acute kidney injury by inhibiting oxidative stress and blocking apoptosis and ferroptosis in mice |
| topic | acute kidney injury oxidative stress antioxidants JP4-039 apoptosis ferroptosis |
| url | https://www.mdpi.com/2076-3921/13/12/1534 |
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