Nanosized titanium dioxide resulted in the activation of TGF‐β/Smads/p38MAPK pathway in renal inflammation and fibration of mice

Abstract

Titanium dioxide nanoparticles (TiO2 NPs) have been demonstrated to damage the kidneys. However, whether chronic nephritis leads to renal fibration or the fibrosis is associated with the activation of TGF-β/Smads/p38MAPK pathway caused by TiO2 NPs exposure is not well understood. Forty male mice were separately exposed to 0, 2.5, 5, or 10 mg/kg body weight TiO2 NPs for 6 months. Renal biochemical functions and levels of TGF-β/Smads/p38MAPK pathway-related markers and extracellular matrix (ECM) expression in the kidneys were investigated. The findings showed that subchronic TiO2 NPs exposure increased levels of urinary creatisix (Cr), N-acetyl-glucosaminidase, and vanin-1, resulted in severe renal inflammation and fibration. Furthermore, TiO2 NP exposure upregulated expression of transforming growth factor-β1 (TGF-β1, 0.07- to 2.72-fold), Smad2 (0.42- to 1.63-fold), Smad3 (0.02- to 1.94-fold), ECM (0.15- to 2.75-fold), α-smooth muscle actin (0.14- to 3.06-fold), p38 mitogen-activated protein kinase (p38MAPK, 0.11- to 3.78-fold), and nuclear factor-κB (0.4- to 2.27-fold), and downregulated Smad7 (0.05- to 0.61-fold) expression in mouse kidney. Subchronic TiO2 NPs exposure induced changes of renal characteristics towards inflammation and fibration may be mediated via TGF-β/Smads/p38MAPK pathway, and the uses of TiO2 NPs should be carried out cautiously, especially in humans. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1452-1461, 2016.

EP4 knockdown alleviates glomerulosclerosis through Smad and MAPK pathways in mesangial cells

“…Smads mediate the signal transduction from TGF-β1. Smad3 is well known as a key regulator of fibrosis in many organ systems, and this is supported by the findings that mice lacking Smad3 are protected against fibrosis in multiple disease models (32)(33)(34). MAPK signaling is able to regulate fibrosis either independently or through cross-talk with Smad pathways (36)(37)(38).…”

“…5C and D). considered to be the classical mechanism for fibrosis in physiological change induced by TGF-β1 (32). To confirm the fibrosis effect in MCs induced by TGF-β1, the level of Smad3 was detected and it was identified that TGF-β1 effectively enhanced the phosphorylation level of Smad3 in both MC genotypes.…”

“…Furthermore, previous research has indicated that there is cross-talk between Smad and MAPK signaling (32). In addition, although both EP2 and EP4 couple with Gs protein to upregulate the level of cAMP, it is EP2 that primarily increases cAMP level (25).…”

“…TGF-β1, a fibrotic stimulus, is able to activate Smad proteins (Smad2 or Smad3) directly to cause renal fibrosis (31)(32)(33)(34). Mitogen-activated protein kinase (MAPK) pathways, which comprise extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38 signaling, have been reported to play a role in inflammatory regulation (35,36), and also contribute to the amplification of transmitted signals to promote cellular processes, including proliferation and differentiation, either in the cytoplasm or nucleus (37,38).…”

Effects of Artesunate prevent nephritis via the Toll-like receptor 4/nuclear factor-κB signaling pathway in rats

“…The TGF-β1 signaling pathway is the most active. TGF-β is a multifunctional polypeptide growth factor that regulates cell proliferation, differentiation and apoptosis by complex receptor signaling pathways in the cell surface (19). TGF-β inhibits proliferation of glomerular epithelial cells and endothelial cells; however, it has a dual role on MCs: It stimulates proliferation at a low concentration, and inhibits proliferation at a high concentration (20).…”