Cytoglobin, a novel globin, plays an antifibrotic role in the kidney.
Cytoglobin (Cygb), a novel member of the globin superfamily, is expressed by fibroblasts in various organs. However, its function remains unknown. Because of its localization, we speculated that a biological role of Cygb may be related to fibrogenesis. To clarify the role of Cygb in kidney fibrosis, we employed the remnant kidney model in rats. Immunohistochemical analysis showed an increase in Cygb expression in parallel with disease progression. To investigate the functional consequence of Cygb upregulation, we established transgenic rats overexpressing rat Cygb. Overexpression of Cygb improved histological injury, preserved renal function, and ameliorated fibrosis, as estimated by the accumulation of collagen I and IV as well as Masson trichrome staining. These protective effects of Cygb were associated with a decrease in nitrotyrosine deposition in the kidney and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion as a marker of oxidative stress. We also performed in vitro studies utilizing a rat kidney fibroblast cell line transiently overexpressing Cygb, an inducible kidney cell transfected with Cygb, and primary cultured fibroblasts isolated from the kidneys of the transgenic rats. These different experimental systems consistently showed that Cygb inhibited collagen synthesis. Furthermore, mutant disruption of heme in Cygb that impaired its antioxidant properties led to the loss of antifibrotic effects, suggesting that Cygb reduces fibrosis via a radical scavenging function. In conclusion, we showed that Cygb plays an important role in protection of the kidney against fibrosis via the amelioration of oxidative stress both in vitro and in vivo. Cygb might represent a good therapeutic target in chronic kidney disease.
Mimura
Imari
I
Div. of Nephrology and Endocrinology, Univ. of Tokyo School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Nangaku
Masaomi
M
Nishi
Hiroshi
H
Inagi
Reiko
R
Tanaka
Tetsuhiro
T
Fujita
Toshiro
T
D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002460:Cell Line; D019070:Cell Lineage; D024141:Collagen Type IV / Q000378:metabolism; D000078842:Cytoglobin; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D005914:Globins / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D008297:Male; D016297:Mutagenesis, Site-Directed; D018384:Oxidative Stress / Q000502:physiology; D010957:Plasmids / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D024141:Collagen Type IV; C000627268:Cygb protein, rat; D000078842:Cytoglobin; D034741:RNA, Small Interfering; D012313:RNA; D005914:Globins