1. Academic Validation
  2. Peptide DR8 suppresses epithelial-to-mesenchymal transition via the TGF-β/MAPK signaling pathway in renal fibrosis

Peptide DR8 suppresses epithelial-to-mesenchymal transition via the TGF-β/MAPK signaling pathway in renal fibrosis

  • Life Sci. 2020 Nov 15;261:118465. doi: 10.1016/j.lfs.2020.118465.
Bochuan Deng 1 Wenle Yang 2 Dan Wang 1 Lu Cheng 1 Lili Bu 1 Jing Rao 2 Jianfeng Zhang 1 Junqiu Xie 3 Bangzhi Zhang 4
Affiliations

Affiliations

  • 1 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China; School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
  • 2 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China.
  • 3 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China. Electronic address: [email protected].
  • 4 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China. Electronic address: [email protected].
Abstract

Aims: Renal fibrosis is a progressive disease that leads to renal dysfunction and end-stage renal failure, and there is currently no specific treatment. Our previous study showed that the 8-residue peptide DR8 (DHNNPQIR) exhibits potent antioxidant and antifibrotic properties, and accumulating evidence suggests that oxidative stress contributes greatly to fibrosis. The effects and mechanisms of DR8 on renal fibrosis remain unknown.

Materials and methods: The effects of DR8 were assessed in a unilateral ureteral obstruction mouse model that received a daily, single-dose subcutaneous injection of 500 μg/kg DR8 for 14 days and in cultured cells (HK-2 and NIH-3T3 cells) treated with 5 ng/mL TGF-β1 and 80 μM DR8. Western blotting, immunohistochemical staining, real-time qPCR and other tools were conducted to study the molecular mechanisms underlying antifibrotic effects.

Key findings: DR8 improved renal function and reduced injury and extracellular matrix (ECM) deposition. Inflammation and oxidative stress were alleviated by DR8 in vivo. DR8 also inhibited the activation of fibroblasts and ECM deposition in HK-2 and NIH-3T3 cells induced by TGF-β1. In addition, epithelial-to-mesenchymal transition (EMT) was inhibited by DR8 both in vivo and in vitro. Mechanistic studies supported that DR8 inhibited ERK and p38 mitogen-activated protein kinase (MAPK) activation. These results indicate that DR8 attenuates renal fibrosis via suppression of EMT by antagonizing the MAPK pathway.

Significance: We provide mechanistic details for a potential therapeutic agent and establish a foundation for peptide therapeutics.

Keywords

DR8; Epithelial-to-mesenchymal transition; MAPK; Renal fibrosis.

Figures
Products