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 streptozotocininduced diabetic apolipoprotein E 2/2 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-a, 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-b-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-kB. These findings suggest that this class of compound is worthy of further study to lessen diabetes complications but that dosage needs consideration.

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

“…This was associated with attenuation of oxidative stress, inflammation, and glomerular and tubulo-interstitial lesions, and partial improvement of renal function confirming the results of recent studies (30)(31)(32). In contrast, dh404 treatment at 10 mg/kg/day dosage resulted in intensification of proteinuria, deterioration of renal function and histological lesions, and amplification of oxidative stress and inflammation, confirming the effects observed in the Zucker rats with diabetic nephropathy and ApoE deficient mice with streptozoticineinduced diabetes [29,33]. Taken together these findings indicate the dose dependent dimorphic actions of Bardoxolone methyl analogs on CKD progression with favorable effect at a low drug dosage and toxic effects at a high dosage.…”

“…These observations point to the possible differences in the drug dosage as the potential cause of the divergent results of the reported studies. This assumption was confirmed by a recent elegant study by Tan et al who showed that dh404, at lower but not higher doses, significantly lessens diabetes-associated 5 atherosclerosis and nephropathy in apolipoprotein E−/− mice with streptozotocin-induced diabetes [33]. In an attempt to explore this possibility and to determine the optimal drug dosage, we conducted a series of preliminary experiments using a wide range of a bardoxolone methyl analog, dh404 dosage (0.5-20 mg/kg/day) in male Sprague Dawley rats.…”

“…It is of note that, many natural Nrf2 inducing phytochemicals have hormetic properties with beneficial effects at nanomolar concentrations and toxic effects at higher concentrations [34,35]. It is, therefore, conceivable that the divergent response to bardoxolone analogues reported in the experimental animals [29][30][31][32][33] represents a shared hormetic property with their natural counterparts. The present study was undertaken to explore the impact of BARD analogue, dh404, dosage on kidney tissue Nrf2-Keap1, NFkB, fibrotic, and oxidative pathways as well as renal structure and function in rats with CKD induced by 5/6 nephrectomy.…”

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

“…Subsequent chemical modifications of CDDO led to the development of the triterpenoid, dihydro‐CDDO‐trifluoroethyl amide (dh404). In a preclinical study using dh404, it could be demonstrated that diabetes‐associated atherosclerosis is significantly attenuated, along with reductions in pro‐inflammatory mediators, MCP‐1, vascular cell adhesion molecule 1 (VCAM‐1) and the p65 subunit of NF‐κB, suggesting that modulations of this pathway by pseudo‐stressors may be a feasible therapeutic strategy to lessen diabetes‐associated CVD 54, 55…”

“…This recently investigated antioxidant‐inflammatory modulator has shown improvements in diabetes‐associated cardiovascular diseases,54 but little is known preclinically about its protective role in diabetic cardiomyopathy. In a model of postmyocardial infarct (MI) remodelling in rats, recent data support a role for dh404 in the protection against adverse ventricular remodelling, as assessed 1 month post‐MI 55.…”