Hypoxia Induces Renal Epithelial Injury and Activates Fibrotic Signaling Through Up-Regulation of Arginase-II

The ureohydrolase, type-II arginase (Arg-II), is a mitochondrial enzyme metabolizing L-arginine into urea and L-ornithine and is highly expressed in renal proximal tubular cells (PTC) and upregulated by renal ischemia. Recent studies reported contradictory results on the role of Arg-II in renal inju...

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Autores principales:	Xiujie Liang, Duilio Michele Potenza, Andrea Brenna, Yiqiong Ma, Zhilong Ren, Xin Cheng, Xiu-Fen Ming, Zhihong Yang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	arginase collagen hypoxia kidney TGFβ1 Physiology QP1-981
Acceso en línea:	https://doaj.org/article/38453dea958844b29ff98fc4d88f7054
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spelling	oai:doaj.org-article:38453dea958844b29ff98fc4d88f70542021-11-19T07:45:51ZHypoxia Induces Renal Epithelial Injury and Activates Fibrotic Signaling Through Up-Regulation of Arginase-II1664-042X10.3389/fphys.2021.773719https://doaj.org/article/38453dea958844b29ff98fc4d88f70542021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphys.2021.773719/fullhttps://doaj.org/toc/1664-042XThe ureohydrolase, type-II arginase (Arg-II), is a mitochondrial enzyme metabolizing L-arginine into urea and L-ornithine and is highly expressed in renal proximal tubular cells (PTC) and upregulated by renal ischemia. Recent studies reported contradictory results on the role of Arg-II in renal injury. The aim of our study is to investigate the function of Arg-II in renal epithelial cell damage under hypoxic conditions. Human renal epithelial cell line HK2 was cultured under hypoxic conditions for 12–48 h. Moreover, ex vivo experiments with isolated kidneys from wild-type (WT) and genetic Arg-II deficient mice (Arg-II–/–) were conducted under normoxic and hypoxic conditions. The results show that hypoxia upregulates Arg-II expression in HK2 cells, which is inhibited by silencing both hypoxia-inducible factors (HIFs) HIF1α and HIF2α. Treatment of the cells with dimethyloxaloylglycine (DMOG) to stabilize HIFα also enhances Arg-II. Interestingly, hypoxia or DMOG upregulates transforming growth factor β1 (TGFβ1) levels and collagens Iα1, which is prevented by Arg-II silencing, while TGFβ1-induced collagen Iα1 expression is not affected by Arg-II silencing. Inhibition of mitochondrial complex-I by rotenone abolishes hypoxia-induced reactive oxygen species (mtROS) and TGFβ1 elevation in the cells. Ex vivo experiments show elevated Arg-II and TGFβ1 expression and the injury marker NGAL in the WT mouse kidneys under hypoxic conditions, which is prevented in the Arg-II–/– mice. Taking together, the results demonstrate that hypoxia activates renal epithelial HIFs-Arg-II-mtROS-TGFβ1-cascade, participating in hypoxia-associated renal injury and fibrosis.Xiujie LiangDuilio Michele PotenzaAndrea BrennaYiqiong MaZhilong RenXin ChengXiu-Fen MingZhihong YangFrontiers Media S.A.articlearginasecollagenhypoxiakidneyTGFβ1PhysiologyQP1-981ENFrontiers in Physiology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	arginase collagen hypoxia kidney TGFβ1 Physiology QP1-981
spellingShingle	arginase collagen hypoxia kidney TGFβ1 Physiology QP1-981 Xiujie Liang Duilio Michele Potenza Andrea Brenna Yiqiong Ma Zhilong Ren Xin Cheng Xiu-Fen Ming Zhihong Yang Hypoxia Induces Renal Epithelial Injury and Activates Fibrotic Signaling Through Up-Regulation of Arginase-II
description	The ureohydrolase, type-II arginase (Arg-II), is a mitochondrial enzyme metabolizing L-arginine into urea and L-ornithine and is highly expressed in renal proximal tubular cells (PTC) and upregulated by renal ischemia. Recent studies reported contradictory results on the role of Arg-II in renal injury. The aim of our study is to investigate the function of Arg-II in renal epithelial cell damage under hypoxic conditions. Human renal epithelial cell line HK2 was cultured under hypoxic conditions for 12–48 h. Moreover, ex vivo experiments with isolated kidneys from wild-type (WT) and genetic Arg-II deficient mice (Arg-II–/–) were conducted under normoxic and hypoxic conditions. The results show that hypoxia upregulates Arg-II expression in HK2 cells, which is inhibited by silencing both hypoxia-inducible factors (HIFs) HIF1α and HIF2α. Treatment of the cells with dimethyloxaloylglycine (DMOG) to stabilize HIFα also enhances Arg-II. Interestingly, hypoxia or DMOG upregulates transforming growth factor β1 (TGFβ1) levels and collagens Iα1, which is prevented by Arg-II silencing, while TGFβ1-induced collagen Iα1 expression is not affected by Arg-II silencing. Inhibition of mitochondrial complex-I by rotenone abolishes hypoxia-induced reactive oxygen species (mtROS) and TGFβ1 elevation in the cells. Ex vivo experiments show elevated Arg-II and TGFβ1 expression and the injury marker NGAL in the WT mouse kidneys under hypoxic conditions, which is prevented in the Arg-II–/– mice. Taking together, the results demonstrate that hypoxia activates renal epithelial HIFs-Arg-II-mtROS-TGFβ1-cascade, participating in hypoxia-associated renal injury and fibrosis.
format	article
author	Xiujie Liang Duilio Michele Potenza Andrea Brenna Yiqiong Ma Zhilong Ren Xin Cheng Xiu-Fen Ming Zhihong Yang
author_facet	Xiujie Liang Duilio Michele Potenza Andrea Brenna Yiqiong Ma Zhilong Ren Xin Cheng Xiu-Fen Ming Zhihong Yang
author_sort	Xiujie Liang
title	Hypoxia Induces Renal Epithelial Injury and Activates Fibrotic Signaling Through Up-Regulation of Arginase-II
title_short	Hypoxia Induces Renal Epithelial Injury and Activates Fibrotic Signaling Through Up-Regulation of Arginase-II
title_full	Hypoxia Induces Renal Epithelial Injury and Activates Fibrotic Signaling Through Up-Regulation of Arginase-II
title_fullStr	Hypoxia Induces Renal Epithelial Injury and Activates Fibrotic Signaling Through Up-Regulation of Arginase-II
title_full_unstemmed	Hypoxia Induces Renal Epithelial Injury and Activates Fibrotic Signaling Through Up-Regulation of Arginase-II
title_sort	hypoxia induces renal epithelial injury and activates fibrotic signaling through up-regulation of arginase-ii
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/38453dea958844b29ff98fc4d88f7054
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Hypoxia Induces Renal Epithelial Injury and Activates Fibrotic Signaling Through Up-Regulation of Arginase-II

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