DR8 (DHNNPQIR), a rapeseed-derived peptide, mitigates fibrosis and muscle atrophy in chronic kidney disease by targeting CNR1-ERK/ELK-1 signaling

  • Peptides. 2025 Dec:194:171456. doi: 10.1016/j.peptides.2025.171456.
Wenli Zhang  1 ,  Yidan Zuo  2 ,  Diyan Xu  3 ,  Yibei Lin  4 ,  Yaoxue Zang  5 ,  Ruyi Chen  6 ,  Mingli Chen  7 ,  Zhen Su  8
Affiliations
  • 1. The First Affiliated Hospital of Wenzhou Medical University, Department of Nephrology, Wenzhou, Zhejiang Province 325000, China. Electronic address: [email protected].
  • 2. The First Affiliated Hospital of Wenzhou Medical University, Department of Nephrology, Wenzhou, Zhejiang Province 325000, China; NHC Key Laboratory of Clinical Nutrition and Intervention, Wenzhou, Zhejiang Province 32500, China. Electronic address: [email protected].
  • 3. The First Affiliated Hospital of Wenzhou Medical University, Department of Nephrology, Wenzhou, Zhejiang Province 325000, China. Electronic address: [email protected].
  • 4. The First Affiliated Hospital of Wenzhou Medical University, Department of Nephrology, Wenzhou, Zhejiang Province 325000, China; The First Affiliated Hospital of Wenzhou Medical University, Department of Pathology, Wenzhou, Zhejiang Province 325000, China. Electronic address: [email protected].
  • 5. The First Affiliated Hospital of Wenzhou Medical University, Department of Nephrology, Wenzhou, Zhejiang Province 325000, China; The First Affiliated Hospital of Wenzhou Medical University, Department of Cardiology, Wenzhou, Zhejiang Province 325000, China. Electronic address: [email protected].
  • 6. The First Affiliated Hospital of Wenzhou Medical University, Department of Nephrology, Wenzhou, Zhejiang Province 325000, China. Electronic address: [email protected].
  • 7. The First Affiliated Hospital of Wenzhou Medical University, Department of Nephrology, Wenzhou, Zhejiang Province 325000, China. Electronic address: [email protected].
  • 8. The First Affiliated Hospital of Wenzhou Medical University, Department of Nephrology, Wenzhou, Zhejiang Province 325000, China. Electronic address: [email protected].
PMID: 41338434 DOI: 10.1016/j.peptides.2025.171456
Abstract

DR8 (DHNNPQIR) is a rapeseed-derived bioactive octapeptide with antioxidant and anti-inflammatory properties, but its therapeutic potential in Chronic Kidney Disease (CKD) and related muscle wasting has not been defined. In this study, we investigated the anti-fibrotic and anti-atrophic efficacy of DR8 using complementary in vitro, transcriptomic, and in vivo approaches. In TGF-β1-stimulated C2C12 myoblasts and HK-2 tubular epithelial cells, DR8 significantly attenuated fibrosis and atrophy by downregulating Cannabinoid Receptor 1 (CNR1) and suppressing ERK-ELK1 activation, leading to restoration of myogenic regulators (MYOD, MYOG) and inhibition of proteolytic E3 Ligases (MuRF-1, MAFbx). Transcriptomic analysis identified CNR1 as a key upstream target mediating these effects. In a 5/6 nephrectomized (5/6Nx) mouse model, systemic administration of DR8 significantly improved renal function, reduced Collagen accumulation, and alleviated skeletal muscle fibrosis and atrophy, accompanied by suppression of CNR1-ERK-ELK1 activation in both organs. Together, these findings demonstrate that DR8 exerts strong renoprotective and myoprotective effects through selective modulation of CNR1-dependent signaling pathways, supporting its potential as a novel peptide therapeutic for CKD-associated fibrosis and muscle wasting.

Keywords
CNR1; Chronic kidney disease; DR8; ERK-ELK1 signaling; Muscle atrophy; Skeletal muscle fibrosis.
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