Protective role of methionine sulfoxide reductase A against ischemia/reperfusion injury in mouse kidney and its involvement in the regulation of trans-sulfuration pathway.
OBJECTIVE
Methionine sulfoxide reductase A (MsrA) and methionine metabolism are associated with oxidative stress, a principal cause of ischemia/reperfusion (I/R) injury. Herein, we investigated the protective role of MsrA against kidney I/R injury and the involvement of MsrA in methionine metabolism and the trans-sulfuration pathway during I/R.


RESULTS
We found that MsrA gene-deleted mice (MsrA(-/-)) were more susceptible to kidney I/R injury than wild-type mice (MsrA(+/+)). Deletion of MsrA enhanced renal functional and morphological impairments, congestion, inflammatory responses, and oxidative stress under I/R conditions. Concentrations of homocysteine and H(2)S in the plasma of control MsrA(-/-) mice were significantly lower than those in control MsrA(+/+) mice. I/R reduced the levels of homocysteine and H(2)S in both MsrA(+/+) and MsrA(-/-) mice, and these reductions were significantly more profound in MsrA(-/-) than in MsrA(+/+) mice. I/R reduced the expression and activities of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), both of which are H(2)S-producing enzymes, in the kidneys. These reductions were more profound in the MsrA(-/-) mice than in the MsrA(+/+)mice.


METHODS
The data provided herein constitute the first in vivo evidence for the involvement of MsrA in regulating methionine metabolism and the trans-sulfuration pathway under normal and I/R conditions.


CONCLUSIONS
Our data demonstrate that MsrA protects the kidney against I/R injury, and that this protection is associated with reduced oxidative stress and inflammatory responses. The data indicate that MsrA regulates H(2)S production during I/R by modulating the expression and activity of the CBS and CSE enzymes.
Department of Anatomy, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Jee In
JI
Kim
Seung Hee
SH
Choi
Kyong-Jin
KJ
Jung
Eujin
E
Lee
Hwa-Young
HY
Kim
Kwon Moo
KM
Park
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006710:Homocysteine / Q000097:blood / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000097:blood / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051150:Methionine Sulfoxide Reductases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*
D000950:Antigens, Ly; C480309:Ly6G antigen, mouse; D006710:Homocysteine; D051150:Methionine Sulfoxide Reductases; D006862:Hydrogen Sulfide