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


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


CONCLUSIONS
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. Antioxid. Redox Signal. 27, 727-741.
1 Department of Anatomy and BK21 Plus, Kyungpook National University School of Medicine , Junggu, Daegu, Republic of Korea.
Mi Ra
MR
Noh
2 Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine , Namgu, Daegu, Republic of Korea.
Ki Young
KY
Kim
1 Department of Anatomy and BK21 Plus, Kyungpook National University School of Medicine , Junggu, Daegu, Republic of Korea.
Sang Jun
SJ
Han
3 Department of Molecular Medicine and MRC, Keimyung University School of Medicine , Dalseogu, Daegu, Republic of Korea.
Jee In
JI
Kim
2 Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine , Namgu, Daegu, Republic of Korea.
Hwa-Young
HY
Kim
1 Department of Anatomy and BK21 Plus, Kyungpook National University School of Medicine , Junggu, Daegu, Republic of Korea.
Kwon Moo
KM
Park
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D004195:Disease Models, Animal; D020558:GTP Phosphohydrolases / Q000378:metabolism; D056304:Genu Valgum; D008715:Methionine / Q000378:metabolism; D051150:Methionine Sulfoxide Reductases / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D018384:Oxidative Stress
C561064:FIS1 protein, mouse; D024101:Mitochondrial Proteins; D008715:Methionine; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse; D002945:Cisplatin
acute kidney injury; apoptosis; cisplatin nephrotoxicity; methionine sulfoxide reductase; mitochondria; oxidative stress