Journal article
The antioxidant and anti-inflammatory activities of avasopasem manganese in age-associated, cisplatin-induced renal injury
Redox biology, Vol.70, 103022
01/2024
DOI: 10.1016/j.redox.2023.103022
PMCID: PMC10821164
PMID: 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.
Experimental design
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.
Details
- Title: Subtitle
- The antioxidant and anti-inflammatory activities of avasopasem manganese in age-associated, cisplatin-induced renal injury
- Creators
- Kranti A. Mapuskar - Radiation Oncology AssociatesCasey F. Pulliam - Radiation Oncology AssociatesAnn Tomanek-Chalkley - Radiation Oncology AssociatesPrerna RastogiHsiang WenSanjana Dayal - Iowa City VA Health Care SystemBenjamin R. GriffinDiana Zepeda-OrozcoAmy L. Sindler - University of IowaCarryn M. Anderson - Radiation Oncology AssociatesRobert BeardsleyEugene P. KennedyDouglas R. Spitz - Radiation Oncology AssociatesBryan G. Allen - Radiation Oncology Associates
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.70, 103022
- DOI
- 10.1016/j.redox.2023.103022
- PMID
- 38215546
- PMCID
- PMC10821164
- NLM abbreviation
- Redox Biol
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Grant note
- DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs, award: I01CX001932; DOI: 10.13039/100006379, name: Office of Research and Development; DOI: 10.13039/100000002, name: National Institutes of Health, award: P01 CA217797, R01 AG049784, T32 CA078586
- Language
- English
- Date published
- 01/2024
- Academic Unit
- Psychiatry; Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Iowa Neuroscience Institute; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Nephrology; Internal Medicine
- Record Identifier
- 9984539758602771
Metrics
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