A derivative of Bardoxolone methyl, dh404, in an inverse dose-dependent manner, lessens diabetes-associated atherosclerosis and improves diabetic kidney disease.

  1. Judy B. de Haan1
  1. 1Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
  2. 2Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
  3. 3Reata Pharmaceuticals Inc. 2801 Gateway Dr, Irving, TX 75063, United States.
  1. Corresponding Author: Judy B. de Haan, E-mail: judy.dehaan{at}bakeridi.edu.au

Abstract

Oxidative stress and inflammation are inextricably linked and play essential roles in the initiation and progression of diabetic complications such as diabetes-associated atherosclerosis and nephropathy. Bolstering antioxidant defences is an important mechanism to lessen oxidative stress and inflammation. In this study, we have used a novel analogue of the Nrf2 agonist bardoxolone methyl, dh404, to investigate its effects on diabetic macrovascular and renal injury in STZ-induced diabetic ApoE-/- 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 pro-inflammatory mediators TNF-α, ICAM-1, VCAM-1 and MCP-1. We demonstrate that dh404 attenuates functional (urinary albumin/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 NRK cells showed that dh404 significantly upregulates Nrf2-responsive genes, HO-1, NQO1 and GSH-S transferase, with inhibition of TGFβ-mediated pro-fibrotic fibronectin, collagen I and pro-inflammatory IL-6. Higher doses of dh404 were associated with increased expression of pro-inflammatory mediators, MCP-1 and NF-κB. These findings suggest that this class of compound is worthy of further study to lessen diabetic complications but that dosage needs consideration.

  • Received November 14, 2013.
  • Accepted April 8, 2014.

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