Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease |
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| Institution: | 1. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA;2. Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA;3. Department of Biological Sciences Purdue University, West Lafayette, IN 47907, USA;4. Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA;5. University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA;1. State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China;2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China;1. College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China;2. Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People''s Republic of China;3. Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People’s Republic of China;1. Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243 122, UP, India;2. Department of Veterinary Microbiology, College of Veterinary & Animal Sciences, G. B. Pant University of Agriculture and Technology, Pantnagar, 263153, UK, India;3. Centre for Wildlife Conservation Management and Disease Surveillance, Indian Veterinary Research Institute, Izatnagar, 243 122, UP, India;4. Division of Pathology, Indian Veterinary Research Institute, Izatnagar, 243 122, UP, India |
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| Abstract: | Oxidative stress and inflammation play a central role in the progression and complications of chronic kidney disease (CKD) and are, in part, due to impairment of the Nrf2 system, which regulates the expression of antioxidant and detoxifying molecules. Natural Nrf2-inducing phytochemicals have been shown to ameliorate kidney disease in experimental animals. However, owing to adverse outcomes a clinical trial of a synthetic Nrf2 activator, bardoxolone methyl (BARD), in CKD patients was terminated. BARD activates Nrf2 via covalent modification of reactive cysteine residues in the Nrf2 repressor molecule, Keap1. In addition to Nrf2, Keap1 suppresses IKKB, the positive regulator of NF-κB. Treatment with a BARD analog, dh404, at 5–20 mg/kg/day in diabetic obese Zucker rats exacerbates, whereas its use at 2 mg/kg/day in 5/6 nephrectomized rats attenuates, CKD progression. We, therefore, hypothesized that deleterious effects of high-dose BARD are mediated by the activation of NF-κB. CKD (5/6 nephrectomized) rats were randomized to receive dh404 (2 or 10 mg/kg/day) or vehicle for 12 weeks. The vehicle-treated group exhibited glomerulosclerosis; interstitial fibrosis and inflammation; activation of NF-κB; upregulation of oxidative, inflammatory, and fibrotic pathways; and suppression of Nrf2 activity and its key target gene products. Treatment with low-dose dh404 restored Nrf2 activity and expression of its target genes, attenuated activation of NF-κB and fibrotic pathways, and reduced glomerulosclerosis, interstitial fibrosis, and inflammation. In contrast, treatment with a high dh404 dosage intensified proteinuria, renal dysfunction, and histological abnormalities; amplified upregulation of NF-κB and fibrotic pathways; and suppressed the Nrf2 system. Thus therapy with BARD analogs exerts a dose-dependent dimorphic impact on CKD progression. |
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| Keywords: | Chronic kidney disease CKD progression Oxidative stress Inflammation Fibrosis Nrf2 Antioxidant system Free radicals |
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