Protective Role of Methionine Sulfoxide Reductase A Against Ischemia/Reperfusion Injury in Mouse Kidney and Its Involvement in the Regulation of Trans-Sulfuration Pathway

Abstract

Aims: 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 transsulfuration 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-b-synthase (CBS) and cystathionine-c-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. Innovation: 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. Conclusion: 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.

Methionine Sulfoxide Reductase A Negatively Controls Microglia-Mediated Neuroinflammation via Inhibiting ROS/MAPKs/NF-κB Signaling Pathways Through a Catalytic Antioxidant Function

“…Taken together, Until now, the role of MsrA in the inflammation remains largely unknown. A recent study has elucidated that deletion of MsrA enhances renal inflammatory responses under I/R conditions (25). Our current findings demonstrate the link between MsrA and microglia-mediated neuroinflammation for the first time.…”

“…S4A-C). NF-jB is usually kept in an inactive form in the cytoplasm through binding an inhibitory protein of the IjB family, which was phosphorylated and degraded under inflammatory stimulation, allowing the phosphorylation of NF-jB p65 subunit and the translocation of NF-jB dimers to the nucleus (25). As shown in Supplementary Figure S4D and E, Tat-rMsrA or nonactive Tat-rMsrA alone (0.5 lM) had no significant effect on the expression of phosphorylated-IjBa (p-IjBa) and p-p65, two widely used indicators of NF-jB activation.…”

Neutral aminoaciduria in cystathionine β-synthase-deficient mice, an animal model of homocystinuria

“…activity assay) (31). Methionine is susceptible to oxidation by ROS under physiological conditions, and the major product is cytotoxic methionine sulfoxide (37,75), and mice lacking its degradation enzyme, methionine sulfoxide reductase A, were more susceptible to renal ischemia-reperfusion injury than wild-type mice (40). Therefore, hyperaccumulation of Met may later cause serious oxidative damage in the kidneys of Cbs Ϫ/Ϫ mice.…”

Methionine sulfoxide reductase A protects hepatocytes against acetaminophen-induced toxicity via regulation of thioredoxin reductase 1 expression

“…Western blot analysis was performed as previously described [8]. Antibodies against MsrA, TXNRD1, Nrf2, heme oxygenase-1 (HO-1), γ-glutamylcysteine ligase (γGCL), lamin B, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were used as previously described.…”

“…With respect to tissue localization, it is highly expressed in the liver and kidney [7]. We have previously shown that MsrA protects the kidney from ischemia/reperfusion injury and fibrosis progression through its antioxidant role [8,9]. Moreover, we recently reported a protective role of MsrA against APAP-induced liver injury [10].…”