Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease

Kranti A Mapuskar; Hsiang Wen; Danniele G Holanda; Prerna Rastogi; Emily Steinbach; Rachel Han; Mitchell C Coleman; Massimo Attanasio; Dennis P Riley; Douglas R Spitz; Bryan G Allen; Diana Zepeda-Orozco

doi:10.1016/j.redox.2018.09.020

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Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease

Journal article

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Peer reviewed

Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease

Kranti A Mapuskar, Hsiang Wen, Danniele G Holanda, Prerna Rastogi, Emily Steinbach, Rachel Han, Mitchell C Coleman, Massimo Attanasio, Dennis P Riley, Douglas R Spitz, …

Redox biology, Vol.20, pp.98-106

09/27/2018

DOI: 10.1016/j.redox.2018.09.020

PMCID: PMC6174865

PMID: 30296702

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Abstract

Severe and recurrent cisplatin-induced acute kidney injury (AKI) as part of standard cancer therapy is a known risk factor for development of chronic kidney disease (CKD). The specific role of superoxide (O )-mediated disruption of mitochondrial oxidative metabolism in CKD after cisplatin treatment is unexplored. Cisplatin is typically administered in weekly or tri-weekly cycles as part of standard cancer therapy. To investigate the role of O in predisposing patients to future renal injury and in CKD, mice were treated with cisplatin and a mitochondrial-specific, superoxide dismutase (SOD) mimetic, GC4419. Renal function, biomarkers of oxidative stress, mitochondrial oxidative metabolism, and kidney injury markers, as well as renal histology, were assessed to evaluate the cellular changes that occur one week and one month (CKD phase) after the cisplatin insult. Cisplatin treatment resulted in persistent upregulation of kidney injury markers, increased steady-state levels of O , increased O -mediated renal tubules damage, and upregulation of mitochondrial electron transport chain (ETC) complex I activity both one week and one month following cisplatin treatment. Treatment with a novel, clinically relevant, small-molecule superoxide dismutase (SOD) mimetic, GC4419, restored mitochondrial ETC complex I activity to control levels without affecting complexes II-IV activity, as well as ameliorated cisplatin-induced kidney injury. These data support the hypothesis that increased mitochondrial O following cisplatin administration, as a result of disruptions of mitochondrial metabolism, may be an important contributor to both AKI and CKD progression.

Mitochondrial metabolism

Superoxide

Superoxide dismutase mimetic

Kidney injury

Cisplatin

Details

Title: Subtitle: Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease
Creators: Kranti A Mapuskar - Department of Radiation Oncology, The University of Iowa, Iowa City, IA, 52242, United States
Hsiang Wen - Division of Pediatric Nephrology, Dialysis and Transplantation, Stead Family Department of Pediatrics, The University of Iowa, Iowa City, IA, 52242, United States
Danniele G Holanda - Department of Pathology, The University of Iowa, Iowa City, IA, 52242, United States
Prerna Rastogi - Department of Pathology, The University of Iowa, Iowa City, IA, 52242, United States
Emily Steinbach - Division of Pediatric Nephrology, Dialysis and Transplantation, Stead Family Department of Pediatrics, The University of Iowa, Iowa City, IA, 52242, United States
Rachel Han - Division of Pediatric Nephrology, Dialysis and Transplantation, Stead Family Department of Pediatrics, The University of Iowa, Iowa City, IA, 52242, United States
Mitchell C Coleman - Department of Orthopedics and Rehabilitation, The University of Iowa, Iowa City, IA, 52242, United States
Massimo Attanasio - Department of Internal Medicine, The University of Iowa, Iowa City, IA, 52242, United States
Dennis P Riley - Galera Therapeutics, Inc., Malvern, PA, United States
Douglas R Spitz - Department of Radiation Oncology, The University of Iowa, Iowa City, IA, 52242, United States
Bryan G Allen - Department of Radiation Oncology, The University of Iowa, Iowa City, IA, 52242, United States
Diana Zepeda-Orozco - Division of Pediatric Nephrology, Dialysis and Transplantation, Stead Family Department of Pediatrics, The University of Iowa, Iowa City, IA, 52242, United States. Electronic address: diana-zepeda-orozco@uiowa.edu
Resource Type: Journal article
Publication Details: Redox biology, Vol.20, pp.98-106
DOI: 10.1016/j.redox.2018.09.020
PMID: 30296702
PMCID: PMC6174865
NLM abbreviation: Redox Biol
ISSN: 2213-2317
eISSN: 2213-2317
Publisher: Netherlands
Grant note: K12 HD027748 / NICHD NIH HHS P30 CA086862 / NCI NIH HHS R01 CA182804 / NCI NIH HHS
Language: English
Date published: 09/27/2018
Academic Unit: Psychiatry; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Pathology; Orthopedics and Rehabilitation; Radiation Oncology; Internal Medicine
Record Identifier: 9984046804902771

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