Rapeseed protein-derived antioxidant peptide RAP alleviates renal fibrosis through MAPK/NF-κB signaling pathways in diabetic nephropathy

Abstract

Mingyan Zhang,1,* Zhibin Yan,1,* Lili Bu,1 Chunmei An,2 Dan Wang,1 Xin Liu,1 Jianfeng Zhang,1 Wenle Yang,2 Bochuan Deng,1 Junqiu Xie,2 Bangzhi Zhang1,2 1Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, China; 2Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China *These authors contributed equally to this work Introduction: Kidney fibrosis is the main pathologic change in diabetic nephropathy (DN), which is the major cause of end-stage renal disease. Current therapeutic strategies slow down but cannot reverse the progression of renal dysfunction in DN. Plant-derived bioactive peptides in foodstuffs are widely used in many fields because of their potential pharmaceutical and nutraceutical benefits. However, this type of peptide has not yet been studied in renal fibrosis of DN. Previous studies have indicated that the peptide YWDHNNPQIR (named RAP), a natural peptide derived from rapeseed protein, has an antioxidative stress effect. The oxidative stress is believed to be associated with DN. The aim of this study was to evaluate the pharmacologic effects of RAP against renal fibrosis of DN and high glucose (HG)-induced mesangial dysfunction. Materials and methods: Diabetes was induced by streptozotocin and high-fat diet in C57BL/6 mice and these mice were treated by subcutaneous injection of different doses of RAP (0.1 mg/kg and 0.5 mg/kg, every other day) or PBS for 12 weeks. Later, functional and histopathologic analyses were performed. Parallel experiments verifying the molecular mechanism by which RAP alleviates DN were carried out in HG-induced mesangial cells (MCs). Results: RAP improved the renal function indices, including 24-h albuminuria, triglyceride, serum creatinine, and blood urea nitrogen levels, but did not lower blood glucose levels in DN mice. RAP also simultaneously attenuated extracellular matrix accumulation in DN mice and HG-induced MCs. Furthermore, RAP reduced HG-induced cell proliferation, but it showed no toxicity in MCs. Additionally, RAP inhibited the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways. Conclusion: RAP can attenuate fibrosis in vivo and in vitro by antagonizing the MAPK and NF-κB pathways. Keywords: antioxidant peptide, RAP, diabetic nephropathy, extracellular matrix, kidney fibrosis, MAPK, NF-κB

Keywords

• RAP
• diabetic nephropathy
• extracellular matrix
• kidney fibrosis
• MAPK
• NF-κB.