Chronic Exposure to Nanoparticulate TiO₂ Causes Renal Fibrosis Involving Activation of the Wnt Pathway in Mouse Kidney

Abstract

Chronic exposure to nano-TiO2 may induce renal fibrosis, and the mechanism of this process is not well understood. Therefore, in this study, mice were administered nano-TiO2 by intragastric feeding for 9 months, and the urinary levels of nephrotoxicity biomarkers, activation of the Wnt pathway, and markers of the epithelial-to-mesenchymal transition (EMT) in the kidneys were investigated. The findings suggested that exposure to nano-TiO2 increased the level of renal titanium accumulation, urinary levels of kidney injury molecule-1 (1.18 ± 0.13- to 3.60 ± 0.41-fold), clusterin (1.40 ± 0.16- to 5.14 ± 0.58-fold), and osteopontin (0.71 ± 0.08- to 2.41 ± 0.29-fold), and increased levels of renal inflammation and fibrosis. Furthermore, nano-TiO2 increased the level of expression of Wnt ligands (Wnt1, Wnt2, Wnt3, Wnt4, Wnt5a, Wnt6, Wnt7a, Wnt9a, Wnt10a, and Wnt11, 0.09 ± 0.02- to 4.84 ± 0.52-fold), Wnt receptors Frizzled (Fz1, Fz5, and Fz7, 0.37 ± 0.04- to 8.57 ± 0.91-fold), and coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (0.73 ± 0.09- to 5.27 ± 0.56-fold) in the kidney. Wnt signaling components induced by nano-TiO2 were corroborated by decreased levels of expression of Wnt antagonist-related markers (Dkk1, Dkk2, Dkk3, Dkk4, and sFRP/FrzB, -0.06 ± 0.01- to -0.87 ± 0.09-fold) and increased levels of expression of Wnt target genes (Abcb1b, cyclin D1, and Myc, 0.03 ± 0.01- to 2.73 ± 0.28-fold) and EMT markers Colla1, Fn, Twist, and α-SMA (0.06 ± 0.02- to 5.80 ± 0.61-fold). These findings indicate that nano-TiO2 induced renal fibrosis that may be mediated via Wnt signaling.