Activation of the RhoA/ROCK pathway contributes to renal fibrosis in offspring rats induced by maternal exposure to di-n-butyl phthalate

  • Toxicology. 2020 Oct;443:152573. doi: 10.1016/j.tox.2020.152573.
Qing Ye  1 ,  Sheng Zhao  2 ,  Yu Zhang  1 ,  Yi-Ming Su  2 ,  Min Chen  2 ,  Jing Zhao  2 ,  Gao-Zhen Jia  2 ,  Bang-Min Han  3 ,  Jun-Tao Jiang  4
Affiliations
  • 1. Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Urology, Shanghai Jiao Tong University, Shanghai, China.
  • 2. Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
  • 4. Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Urology, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
PMID: 32860865 DOI: 10.1016/j.tox.2020.152573
Abstract

Maternal exposure to di-n-butyl phthalate (DBP) can cause renal fibrosis in adult offspring rats. However, its underlying mechanisms have not yet been fully understood. In this study, we investigated whether the RhoA/ROCK pathway plays an important role in offspring renal fibrosis induced by maternal exposure to DBP. Our results showed that maternal exposure to DBP (850 mg/kg/day orally feeding during gestational days 14-18) activated the RhoA/ROCK pathway and induced epithelial-mesenchymal transition (EMT) in kidneys of offspring rats. Compared with the control group treated with normal saline, EMT in the kidneys of offspring rats undergoing 8 weeks of ROCK Inhibitor Y-27632 treatment (at a dose of 30 mg/kg) was significantly inhibited, the degree of renal fibrosis was significantly reduced, and the renal function was significantly improved. DBP (10 μmol/L) activated the RhoA/ROCK pathway and induced EMT in NRK-52E cells in vitro. Both 5 μM and 10 μM Y-27632, a ROCK Inhibitor, significantly reduced the EMT of NRK-52E cells. Taken together, our findings suggest that the RhoA/ROCK pathway plays an important role in the pathogenesis of renal fibrosis in offspring rats induced by maternal exposure to DBP via promoting EMT of renal tubular epithelial cells.

Keywords
Di-n-butyl phthalate; Epithelial-mesenchymal transition; ROCK; Renal fibrosis; Y-27632.
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