Open AccessNADPH oxidase 4 mediates TGF-β1/Smad signaling pathway induced acute kidney injury in hypoxia
Author(s) -
Sung-Kwon Cho,
SeongLan Yu,
Jaeku Kang,
Bo Young Jeong,
Hoi Young Lee,
Chang Gyo Park,
Yang Yu,
Dong-Chan Jin,
WonMin Hwang,
Sung-Ro Yun,
Ho Seung Song,
Moon Hyang Park,
Se-Hee Yoon
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0219483
Subject(s) - nox4 , nicotinamide adenine dinucleotide phosphate , smad , nadph oxidase , nox1 , signal transduction , acute kidney injury , kidney , microbiology and biotechnology , apoptosis , hypoxia (environmental) , renal ischemia , biology , cancer research , chemistry , reperfusion injury , reactive oxygen species , medicine , endocrinology , oxidase test , ischemia , biochemistry , enzyme , organic chemistry , oxygen
Hypoxia is an important cause of acute kidney injury (AKI) in various conditions because kidneys are one of the most susceptible organs to hypoxia. In this study, we investigated whether nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase 4 (Nox4) plays a role in hypoxia induced AKI in a cellular and animal model. Expression of Nox4 in cultured human renal proximal tubular epithelial cells (HK-2) was significantly increased by hypoxic stimulation. TGF-β1 was endogenously secreted by hypoxic HK-2 cells. SB4315432 (a TGF-β1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells through the Smad-dependent cell signaling pathway. Silencing of Nox4 using Nox4 siRNA and pharmacologic inhibition with GKT137831 (a specific Nox1/4 inhibitor) reduced the production of ROS and attenuated the apoptotic pathway. In addition, knockdown of Nox4 increased cell survival in hypoxic HK-2 cells and pretreatment with GKT137831 reproduce these results. This study demonstrates that hypoxia induces HK-2 cell apoptosis through a signaling pathway involving TGF-β1 via Smad pathway induction of Nox4-dependent ROS generation. In an ischemia/reperfusion rat model, pretreatment of GKT137831 attenuated ischemia/reperfusion induced acute kidney injury as indicated by preserved kidney function, attenuated renal structural damage and reduced apoptotic cells. Therapies targeting Nox4 may be effective against hypoxia-induced AKI.