The antioxidant and anti-inflammatory activities of avasopasem manganese in age-associated, cisplatin-induced renal injury.
Redox Biol
; 70: 103022, 2024 Apr.
Article
en En
| MEDLINE
| ID: mdl-38215546
ABSTRACT
PURPOSE:
Cisplatin contributes to acute kidney injury (AKI) and chronic kidney disease (CKD) that occurs with greater frequency and severity in older patients. Age-associated cisplatin sensitivity in human fibroblasts involves increased mitochondrial superoxide produced by older donor cells. EXPERIMENTALDESIGN:
Young and old C57BL/6 J murine models of cisplatin-induced AKI and CKD were treated with the SOD mimetic avasopasem manganese to investigate the potential antioxidant and anti-inflammatory effects. Adverse event reporting from a phase 2 and a phase 3 randomized clinical trial (NCT02508389 and NCT03689712) conducted in patients treated with cisplatin and AVA was determined to have established the incidence and severity of AKI.RESULTS:
Cisplatin-induced AKI and CKD occurred in all mice, however, was more pronounced in older mice. AVA reduced cisplatin-induced mortality, AKI, and CKD, in older animals. AVA also alleviated cisplatin-induced alterations in mitochondrial electron transport chain (ETC) complex activities and NADPH Oxidase 4 (NOX4) and inhibited the increased levels of the inflammation markers, TNFα, IL1, ICAM-1, and VCAM-1. Analysis of age-stratified subjects treated with cisplatin from clinical trials (NCT02508389, NCT03689712) also supported that the incidence of AKI increased with age and AVA reduced age-associated therapy-induced adverse events (AE), including hypomagnesemia, increased creatinine, and AKI.CONCLUSIONS:
Older mice and humans are more susceptible to cisplatin-induced kidney injury, and treatment with AVA mitigates age-associated damage. Mitochondrial ETC and NOX4 activities represent sources of superoxide production contributing to cisplatin-induced kidney injury, and pro-inflammatory cytokine production and endothelial dysfunction may also be increased by superoxide formation.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Compuestos Organometálicos
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Insuficiencia Renal Crónica
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Lesión Renal Aguda
Tipo de estudio:
Clinical_trials
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Risk_factors_studies
Límite:
Aged
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Animals
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Humans
Idioma:
En
Revista:
Redox Biol
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos