title: Derivative of bardoxolone methyl, dh404, in an inverse dose-dependent manner lessens diabetes-associated atherosclerosis and improves diabetic kidney disease.
abstract: Oxidative stress and inflammation are inextricably linked and play essential roles in the initiation and progression of diabetes complications such as diabetes-associated atherosclerosis and nephropathy. Bolstering antioxidant defenses is an important mechanism to lessen oxidative stress and inflammation. In this study, we have used a novel analog of the NFE2-related factor 2 (Nrf2) agonist bardoxolone methyl, dh404, to investigate its effects on diabetic macrovascular and renal injury in streptozotocin-induced diabetic apolipoprotein E(-/-) mice. We show that dh404, at lower but not higher doses, significantly lessens diabetes-associated atherosclerosis with reductions in oxidative stress (in plasma, urine, and vascular tissue) and proinflammatory mediators tumor necrosis factor-α, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemotactic protein-1 (MCP-1). We demonstrate that dh404 attenuates functional (urinary albumin-to-creatinine ratio) and structural (mesangial expansion) glomerular injury and improves renal tubular injury. Liver functional and structural studies showed that dh404 is well tolerated. Complementary in vitro studies in normal rat kidney cells showed that dh404 significantly upregulates Nrf2-responsive genes, heme oxygenase-1, NAD(P)H quinone oxidoreductase 1, and glutathione-S transferase, with inhibition of transforming growth factor-β-mediated profibrotic fibronectin, collagen I, and proinflammatory interleukin-6. Higher doses of dh404 were associated with increased expression of proinflammatory mediators MCP-1 and nuclear factor-κB. These findings suggest that this class of compound is worthy of further study to lessen diabetes complications but that dosage needs consideration.
authors.affiliation: Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Sih Min
authors.initials: SM
authors.lastname: Tan
authors.affiliation: Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Arpeeta
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Nada
authors.initials: N
authors.lastname: Stefanovic
authors.affiliation: Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Derek Y C
authors.initials: DY
authors.lastname: Yuen
authors.affiliation: Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Tom C
authors.initials: TC
authors.lastname: Karagiannis
authors.affiliation: Reata Pharmaceuticals, Inc., Irving, TX.
authors.forename: Colin
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Reata Pharmaceuticals, Inc., Irving, TX.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Ward
authors.affiliation: Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.affiliation: Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia judy.dehaan@bakeridi.edu.au.
authors.forename: Judy B
authors.initials: JB
authors.lastname: de Haan
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D007668:Kidney / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000819:agonists; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats
chemical_list: D001057:Apolipoproteins E; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C547749:dh404 compound; D009828:Oleanolic Acid