Therapeutic potential of digitoflavone on diabetic nephropathy: nuclear factor erythroid 2-related factor 2-dependent anti-oxidant and anti-inflammatory effect.

Yang Yang,Zhiying Teng,Xiaolan Cheng,Chunping Hu,Jie Yang,Wuguang Lu,Xiaoyan Sun,Xueting Cai,Yuanzhang Yao,Gang Chen,Xiaoning Wang,Peng Cao

doi:10.1038/srep12377

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a therapeutic target in many diseases, because it can induce antioxidant enzymes and other cytoprotective enzymes. Moreover, some Nrf2 activators have strong anti-inflammatory activities. Oxidative stress and inflammation are major components involved in the pathology of diabetic nephropathy. In the present study, we evaluated the Nrf2-dependent anti-oxidative and anti-inflammatory effects of digitoflavone in streptozotocin-induced diabetic nephropathy. The molecular mechanisms of digitoflavone were investigated in vitro using SV40-transformed mouse mesangial cells (SV40-Mes13). For the in vivo experiment, diabetes was induced in Nrf2+/+ and Nrf2−/− mice by STZ injection, and digitoflavone was administered 2 weeks after the STZ injection. Digitoflavone induced Nrf2 activation and decreased oxidative damage, inflammation, TGF-β1 expression, extracellular matrix protein expression, and mesangial cell hyperplasia in SV40-Mes13 cells. Digitoflavone-treated Nrf2+/+ mice, but not Nrf2−/− mice, showed attenuated common metabolic disorder symptoms, improved renal performance, minimized pathological alterations, and decreased oxidative damage, inflammatory gene expression, inflammatory cell infiltration, TGF-β1 expression, and extracellular matrix protein expression. Our results show that the anti-oxidative and anti-inflammatory effects of digitoflavone are mediated by Nrf2 activation and that digitoflavone can be used therapeutically to improve metabolic disorders and relieve renal damage induced by diabetes.

Highlights

Nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a therapeutic target in many diseases, because it can induce antioxidant enzymes and other cytoprotective enzymes
Chronic hyperglycemia is a major initiator of diabetic nephropathy (DN)[2]; current therapies aimed at lowering blood glucose do not prevent the ultimate progression of DN, and co-treatment with renoprotective drugs often results in toxicity, limiting their efficacy
Oxidative stress contributes to the onset and pathogenesis of diabetic nephropathy, and high glucose-induced renal damage is associated with excessive production of reactive oxygen species (ROS) under hyperglycemic conditions in vitro[2,8]

Summary

Introduction

Nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a therapeutic target in many diseases, because it can induce antioxidant enzymes and other cytoprotective enzymes. The Nrf2-Keap[1] (nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1) system is one of the most critical cytoprotective mechanisms protecting the body against oxidative stress, and it plays an important role in reducing inflammation[11,12,13,14]. It regulates intracellular antioxidants, phase II detoxifying enzymes, and many other proteins that detoxify xenobiotics and neutralize ROS, and promotes cell survival and maintains cellular redox homeostasis[15]. We found that digitoflavone produces several biological effects, including induction of cell cycle arrest, angiogenesis inhibition, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κ B) down-regulation in apoptosis, and Nrf[2] activation in chemoprevention[27,28,29,30]

Methods

Results

Conclusion