Derivative of bardoxolone methyl, dh404, in an inverse dose-dependent manner lessens diabetes-Associated atherosclerosis and improves diabetic kidney disease

Sih Min Tan, Arpeeta Sharma, Nada Stefanovic, Derek Y C Yuen, Tom C. Karagiannis, Colin Meyer, Keith W. Ward, Mark E. Cooper, Judy B. De Haan

Research output: Contribution to journalArticleResearchpeer-review

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 E2/2 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. 

Original languageEnglish
Pages (from-to)3091-3103
Number of pages13
JournalDiabetes
Volume63
Issue number9
DOIs
Publication statusPublished - Sep 2014
Externally publishedYes

Cite this

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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 streptozotocininduced diabetic apolipoprotein E2/2 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. ",
author = "Tan, {Sih Min} and Arpeeta Sharma and Nada Stefanovic and Yuen, {Derek Y C} and Karagiannis, {Tom C.} and Colin Meyer and Ward, {Keith W.} and Cooper, {Mark E.} and {De Haan}, {Judy B.}",
year = "2014",
month = "9",
doi = "10.2337/db13-1743",
language = "English",
volume = "63",
pages = "3091--3103",
journal = "Diabetes",
issn = "0012-1797",
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Derivative of bardoxolone methyl, dh404, in an inverse dose-dependent manner lessens diabetes-Associated atherosclerosis and improves diabetic kidney disease. / Tan, Sih Min; Sharma, Arpeeta; Stefanovic, Nada; Yuen, Derek Y C; Karagiannis, Tom C.; Meyer, Colin; Ward, Keith W.; Cooper, Mark E.; De Haan, Judy B.

In: Diabetes, Vol. 63, No. 9, 09.2014, p. 3091-3103.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Derivative of bardoxolone methyl, dh404, in an inverse dose-dependent manner lessens diabetes-Associated atherosclerosis and improves diabetic kidney disease

AU - Tan, Sih Min

AU - Sharma, Arpeeta

AU - Stefanovic, Nada

AU - Yuen, Derek Y C

AU - Karagiannis, Tom C.

AU - Meyer, Colin

AU - Ward, Keith W.

AU - Cooper, Mark E.

AU - De Haan, Judy B.

PY - 2014/9

Y1 - 2014/9

N2 - 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 E2/2 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. 

AB - 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 E2/2 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. 

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U2 - 10.2337/db13-1743

DO - 10.2337/db13-1743

M3 - Article

VL - 63

SP - 3091

EP - 3103

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -