Protective role and the underlying mechanism of methionine sulfoxide reductase A against kidney ischemia/reperfusion injury in mouse

JI Kim1,2, KM Park1. 1Kyungpook National University School of Medicine, Department of Anatomy, Daegu700-422, Republic of Korea, 2Cardiovascular Research Institute Kyungpook National University, Daegu 700-422, Republic of Korea

Methionine sulfoxide reductase A (MsrA) reduces free and protein-based methionine-S-sulfoxide back to methionine. MsrA and methionine metabolism are associated with oxidative stress, a principal cause of ischemia/reperfusion (I/R) injury. Here, we investigated the role of MsrA against kidney I/R injury and the underlying mechanisms. MsrA gene-deleted (MsrA − / − ) or wild-type (MsrA+/+ ) mice were generated by breeding heterozygous MsrA knockout mice that were of mixed background of 129/SvJ and C57BL/6. 8 to 10 week-old MsrA − / − or MsrA+/+ male mice weighing 20 to 25 g were subjected to sham or 30 m of bilateral renal ischemia and 24 h reperfusion. 4-10 independent experiments were performed for each group. Statistical differences among groups were calculated using analysis of variance (ANOVA) followed by least-significant difference post hoc comparisons using SPSS 12.0. As results, I/R reduced expression and activity of MsrA in the kidney. Plasma creatinine level of MsrA − / − was 1.94±0.01 and that of MsrA+/+ was 1.44±0.16 indicating that MsrA − / − were more susceptible to kidney I/R injury than MsrA+/+ . Deletion of MsrA enhanced renal functional and morphological impairments, congestion, inflammatory responses, and oxidative stress under I/R conditions. Concentrations of H2S in the plasma and kidney of control MsrA − / − mice were significantly lower than those in control MsrA+/+ mice. I/R reduced the expression and activities of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), both of which are H2S-producing enzymes, in the kidneys. I/R reduced the plasma level of homocysteine, which is a metabolite of methionine and a substrate for H2S-producing enzymes, in both MsrA+/+ and MsrA − / − mice. These reductions were significantly more profound in MsrA − / − than in MsrA+/+ mice. I/R reduced kidney level of homocysteine only in the MsrA − / − mice. In conclusion, our data demonstrate that MsrA protects the kidney against I/R injury through modulating the methionine metabolism and H2S production resulting in reduced oxidative stress. To our knowledge, our data provide the first in vivo evidence for the protective role of MsrA in regulating the methionine metabolism and transsulfuration pathway in the kidney I/R providing MsrA as a noble target for the treatment of I/R injury.