title: Biliverdin Reductase A (BVRA) Mediates Macrophage Expression of Interleukin-10 in Injured Kidney.
abstract: Biliverdin reductase A is an enzyme, with serine/threonine/tyrosine kinase activation, converting biliverdin (BV) to bilirubin (BR) in heme degradation pathway. It has been reported to have anti-inflammatory and antioxidant effect in monocytes and human glioblastoma. However, the function of BVRA in polarized macrophage was unknown. This study aimed to investigate the effect of BVRA on macrophage activation and polarization in injured renal microenvironment. Classically activated macrophages (M1macrophages) and alternative activation of macrophages (M2 macrophages) polarization of murine bone marrow derived macrophage was induced by GM-CSF and M-CSF. M1 polarization was associated with a significant down-regulation of BVRA and Interleukin-10 (IL-10), and increased secretion of TNF-α. We also found IL-10 expression was increased in BVRA over-expressed macrophages, while it decreased in BVRA knockdown macrophages. In contrast, BVRA over-expressed or knockdown macrophages had no effect on TNF-α expression level, indicating BVRA mediated IL-10 expression in macrophages. Furthermore, we observed in macrophages infected with recombinant adenoviruses BVRA gene, which BVRA over-expressed enhanced both INOS and ARG-1 mRNA expression, resulting in a specific macrophage phenotype. Through in vivo study, we found BVRA positive macrophages largely existed in mice renal ischemia perfusion injury. With the treatment of the regular cytokines GM-CSF, M-CSF or LPS, excreted in the injured renal microenvironment, IL-10 secretion was significantly increased in BVRA over-expressed macrophages. In conclusion, the BVRA positive macrophage is a source of anti-inflammatory cytokine IL-10 in injured kidney, which may provide a potential target for treatment of kidney disease.
authors.affiliation: Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China. christina_418@126.com.
authors.forename: Zhizhi
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China. pgc2008@sina.com.
authors.forename: Guangchang
authors.initials: G
authors.lastname: Pei
authors.affiliation: Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China. 15939991300@163.com.
authors.forename: Pengge
authors.initials: P
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China. amy19861203@126.com.
authors.forename: Juan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China. zhufm1988@163.com.
authors.forename: Fengmin
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China. 18702765105@163.com.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China. nishuihan2003@163.com.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China. yaoyingkk@126.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China. zengrui@tjh.tjmu.edu.cn.
authors.forename: Rui
authors.initials: R
authors.lastname: Zeng
authors.affiliation: Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China. liaowh126@126.com.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Liao
authors.affiliation: Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, Hubei, China. xugang@tjh.tjmu.edu.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
mesh_terms: D000818:Animals; D002460:Cell Line; D016764:Cell Polarity; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000276:immunology*; D051437:Renal Insufficiency / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000473:pathology*
chemical_list: D008070:Lipopolysaccharides; D016753:Interleukin-10; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase
keywords: biliverdin reductase; interleukin-10; macrophages