Huang K.-T.Wu C.-T.KUO-HOW HUANGWEI-CHOU LINCHANG-MU CHENGuan S.-S.CHIH-KANG CHIANGLiu S.-H.2022-03-042022-03-0420150893-228Xhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84924904522&doi=10.1021%2ftx500287f&partnerID=40&md5=0b063f347f7470e198a040457ef8678ahttps://scholars.lib.ntu.edu.tw/handle/123456789/596135Titanium dioxide nanoparticles (Nano-TiO2) are gradually being used extensively in clinical settings, industry, and daily life. Accumulation studies showed that Nano-TiO2 exposure is able to cause injuries in various animal organs, including the lung, liver, spleen, and kidney. However, it remains unclear whether exposure of Nano-TiO2 by inhalation causes renal fibrosis. Here, we investigated the role of reactive oxygen species (ROS)/reactive nitrogen species (RNS) related signaling molecules in chronic renal damage after Nano-TiO2 inhalation in mice. Mice were treated with Nano-TiO2 (0.1, 0.25, and 0.5 mg/week) or microparticle-TiO2 (0.5 mg/week) by nonsurgical intratracheal instillation for 4 weeks. The results showed that Nano-TiO2 inhalation increased renal pathological changes in a dose-dependent manner. No renal pathological changes were observed in microparticle-TiO2-instilled mice. Nano-TiO2 (0.5 mg/week) possessed the ability to precipitate in the kidneys, determined by transmission electron microscopy and increased serum levels of blood urea nitrogen. The expressions of markers of ROS/RNS and renal fibrosis markers, including nitrotyrosine, inducible nitric oxide synthase, hypoxia inducible factor-1α (HIF-1α), heme oxygenase 1, transforming growth factor-β (TGFβ), and collagen I, determined by immunohistochemical staining were increased in the kidneys. Furthermore, Nano-TiO2-induced renal injury could be mitigated by iNOS inhibitor aminoguanidine and ROS scavenger N-acetylcysteine treatment in transcription level. The in vitro experiments showed that Nano-TiO2 significantly and dose-dependently increased the ROS production and the expressions of HIF-1α and TGFβ in human renal proximal tubular cells, which could be reversed by N-acetylcysteine treatment. Taken together, these results suggest Nano-TiO2 inhalation might induce renal fibrosis through a ROS/RNS-related HIF-1α-upregulated TGF-β signaling pathway. ? 2014 American Chemical Society.[SDGs]SDG33 nitrotyrosine; acetylcysteine; collagen type 1; heme oxygenase 1; hypoxia inducible factor 1alpha; inducible nitric oxide synthase; reactive nitrogen species; reactive oxygen metabolite; titanium dioxide nanoparticle; transforming growth factor beta; collagen type 1; Hif1a protein, mouse; hypoxia inducible factor 1alpha; inducible nitric oxide synthase; interleukin 1beta; messenger RNA; metal nanoparticle; Nos2 protein, mouse; titanium; titanium dioxide; transforming growth factor beta; tumor necrosis factor alpha; animal experiment; animal model; animal tissue; Article; brush border; cell organelle; controlled study; extracellular matrix; granulocyte; human; human cell; immunohistochemistry; in vitro study; inhalation; kidney; kidney fibrosis; lung parenchyma; mouse; nonhuman; oxidative stress; protein expression; signal transduction; transmission electron microscopy; urea nitrogen blood level; animal; biosynthesis; cell line; chemically induced; drug effects; fibrosis; genetics; inhalational drug administration; Institute for Cancer Research mouse; kidney disease; male; metabolism; oxidative stress; pathology; Animalia; Mus; Administration, Inhalation; Animals; Cell Line; Collagen Type I; Fibrosis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-1beta; Kidney; Kidney Diseases; Male; Metal Nanoparticles; Mice, Inbred ICR; Nitric Oxide Synthase Type II; Oxidative Stress; RNA, Messenger; Titanium; Transforming Growth Factor beta; Tumor Necrosis Factor-alphajournal article10.1021/tx500287f254061002-s2.0-84924904522