Derivative of Bardoxolone Methyl, dh404, in an Inverse Dose-Dependent Manner Lessens Diabetes-Associated Atherosclerosis and Improves Diabetic Kidney Disease

• Published in: Diabetes (New York, N.Y.) Vol. 63; no. 9; pp. 3091 - 3103
• Main Authors: SIH MIN TAN, SHARMA, Arpeeta, STEFANOVIC, Nada, YUEN, Derek Y. C, KARAGIANNIS, Tom C, MEYER, Colin, WARD, Keith W, COOPER, Mark E, DE HAAN, Judy B
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.09.2014
• Subjects: Animals; Aorta - metabolism; Apolipoproteins E - deficiency; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - prevention & control; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells; Collagen; Diabetes Mellitus, Experimental - metabolism; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - drug therapy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Kidney - pathology; Kidney - physiology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Molecules; NF-E2-Related Factor 2 - agonists; Oleanolic Acid - administration & dosage; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - therapeutic use; Oxidative stress; Oxidative Stress - drug effects; Rats; Rodents; Endocrinopathy; Vascular disease; Kidney disease; Urinary system disease; Diabetes mellitus; Atherosclerosis; Cardiovascular disease
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db13-1743

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.