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Methionine Sulfoxide Reductase A Deficiency Exacerbates Cisplatin-Induced Nephrotoxicity via Increased Mitochondrial Damage and Renal Cell Death

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Author(s)
Mi Ra NohKi Young KimSang Jun HanJee In KimHwa-Young KimKwon Moo Park
Keimyung Author(s)
Kim, Jee In
Department
Dept. of Molecular Medicine (분자의학)
Journal Title
Antioxidants & Redox Signaling
Issued Date
2017
Volume
27
Issue
11
Keyword
acute kidney injuryapoptosiscisplatin nephrotoxicitymethionine sulfoxide reductasemitochondriaoxidative stress
Abstract
AIMS:
Methionine sulfoxide reductase A (MsrA), which is abundantly localized in the mitochondria, reduces methionine-S-sulfoxide, scavenging reactive oxygen species (ROS). Cisplatin, an anticancer drug, accumulates at high levels in the mitochondria of renal cells, causing mitochondrial impairment that ultimately leads to nephrotoxicity. Here, we investigated the role of MsrA in cisplatin-induced mitochondrial damage and kidney cell death using MsrA gene-deleted (MsrA-/-) mice.

RESULTS:
Cisplatin injection resulted in increases of ROS production, methionine oxidation, and oxidative damage in the kidneys. This oxidative stress was greater in MsrA-/- mouse kidneys than in wild-type (MsrA+/+) mouse kidneys. MsrA gene deletion exacerbated cisplatin-induced reductions in the expression and activity of MsrA and MsrBs, and the expression of thioredoxin 1, glutathione peroxidase 1 and 4, mitochondrial superoxide dismutase, cystathionine-β-synthase, and cystathionine-γ-lyase. Cisplatin induced swelling, cristae loss, and fragmentation of mitochondria with increased lipid peroxidation, more so in MsrA-/- than in MsrA+/+ kidneys. The ratio of mitochondrial fission regulator (Fis1) to fusion regulator (Opa1) was higher in MsrA-/- than MsrA+/+ mice. MsrA deletion exacerbated cisplatin-induced increases in Bax to Bcl-2 ratio, cleaved caspase-3 level, and apoptosis, whereas MsrA overexpression attenuated cisplatin-induced oxidative stress and apoptosis.

INNOVATION:
MsrA gene deletion in mice exacerbates cisplatin-induced renal injury through increases of mitochondrial susceptibility, whereas MsrA overexpression protects cells against cisplatin.

CONCLUSION:
This study demonstrates that MsrA protects kidney cells against cisplatin-induced methionine oxidation, oxidative stress, mitochondrial damage, and apoptosis, suggesting that MsrA could be a useful target protein for the treatment of cisplatin-induced nephrotoxicity.
Keimyung Author(s)(Kor)
김지인
Publisher
School of Medicine (의과대학)
Citation
Mi Ra Noh et al. (2017). Methionine Sulfoxide Reductase A Deficiency Exacerbates Cisplatin-Induced Nephrotoxicity via Increased Mitochondrial Damage and Renal Cell Death. Antioxidants & Redox Signaling, 27(11), 727–741. doi: 10.1089/ars.2016.6874
Type
Article
ISSN
1523-0864
Source
https://www.liebertpub.com/doi/10.1089/ars.2016.6874
DOI
10.1089/ars.2016.6874
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/41352
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Molecular Medicine (분자의학)
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