title: Methionine sulfoxide reductase A deficiency exacerbates progression of kidney fibrosis induced by unilateral ureteral obstruction.
abstract: Methionine sulfoxide reductase A (MsrA), which stereospecifically catalyzes the reduction of methionine-S-sulfoxide, is an important reactive oxygen species (ROS) scavenger. Tissue fibrosis is a maladaptive repair process following injury, associated with oxidative stress. In this study, we investigated the role of MsrA in unilateral ureteral obstruction (UUO)-induced kidney fibrosis and its underlying mechanisms by using MsrA gene-deleted mice (MsrA(-/-)). MsrA deletion increased collagen deposition in the interstitium and the expression of collagen III and α-smooth muscle actin in the UUO kidneys, indicating that MsrA deficiency exacerbated the progression of UUO-induced kidney fibrosis. UUO reduced the kidney expression of MsrA, MsrB1, and MsrB2, thereby decreasing MsrA and MsrB activity. UUO increased hydrogen peroxide and lipid peroxidation levels and the ratio of oxidized glutathione (GSSG) to total glutathione (GSH) in the kidneys. The UUO-induced elevations in the levels of these oxidative stress markers and leukocyte markers were much higher in the MsrA(-/-) than in the MsrA(+/+) kidneys, the latter suggesting that the exacerbated kidney fibrosis in MsrA(-/-) mice was associated with enhanced inflammatory responses. Collectively, our data suggest that MsrA plays a protective role in the progression of UUO-induced kidney fibrosis via suppression of fibrotic responses caused by oxidative stress and inflammation.
authors.affiliation: Department of Molecular Medicine and MRC, Keimyung University School of Medicine, Daegu 705-717, Republic of Korea.
authors.forename: Jee In
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Department of Anatomy and BK21 Plus Program, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea.
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Noh
authors.affiliation: Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu 705-717, Republic of Korea.
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Department of Anatomy and BK21 Plus Program, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea.
authors.forename: Hee-Seong
authors.initials: HS
authors.lastname: Jang
authors.affiliation: Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu 705-717, Republic of Korea. Electronic address: hykim@ynu.ac.kr.
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Department of Anatomy and BK21 Plus Program, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea. Electronic address: kmpark@knu.ac.kr.
authors.forename: Kwon Moo
authors.initials: KM
authors.lastname: Park
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D018450:Disease Progression; D005355:Fibrosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051150:Methionine Sulfoxide Reductases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications*
chemical_list: D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D002374:Catalase; D013482:Superoxide Dismutase; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; D005978:Glutathione
keywords: Fibrosis; Inflammation; Methionine sulfoxide reductase; MsrA; Oxidative stress; Ureteral obstruction