title: Biliverdin reductase mediates hypoxia-induced EMT via PI3-kinase and Akt.
abstract: Chronic hypoxia in the renal parenchyma is thought to induce epithelial-to-mesenchymal transition (EMT), leading to fibrogenesis and ultimately end-stage renal failure. Biliverdin reductase, recently identified as a serine/threonine/tyrosine kinase that may activate phosphatidylinositol 3-kinase (PI3K) and Akt, is upregulated in response to reactive oxygen species that may accompany hypoxia. We investigated this potential role of biliverdin reductase in hypoxia-induced renal tubular EMT. Expression of biliverdin reductase was upregulated in a human proximal tubule cell line (HK-2) cultured in hypoxic conditions (1% O2), and this was accompanied by reduced expression of E-cadherin and increased expression of the mesenchymal marker vimentin. Inhibiting PI3K reversed these changes, consistent with EMT. In normoxic conditions, overexpression of biliverdin reductase promoted similar characteristics of EMT, which were also reversed by inhibiting PI3K. Furthermore, using small interfering RNA (siRNA) to knockdown biliverdin reductase, we demonstrated that the enzyme associates with phosphorylated Akt and mediates the hypoxia-induced EMT phenotype. In vivo, expression of biliverdin reductase increased in the tubular epithelia of 5/6-nephrectomized rats, and immunohistochemistry of serial sections demonstrated similar localization of phosphorylated Akt and biliverdin reductase. In conclusion, biliverdin reductase mediates hypoxia-induced EMT through a PI3K/Akt-dependent pathway.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zeng
authors.forename: Ying
authors.initials: Y
authors.lastname: Yao
authors.forename: Min
authors.initials: M
authors.lastname: Han
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Zhao
authors.forename: Xiao-Cheng
authors.initials: XC
authors.lastname: Liu
authors.forename: Juncheng
authors.initials: J
authors.lastname: Wei
authors.forename: Yun
authors.initials: Y
authors.lastname: Luo
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.forename: Shixuan
authors.initials: S
authors.lastname: Wang
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000201:enzymology*; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000201:enzymology; D009392:Nephrectomy; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt