Limits...
Nrf2 activators as attractive therapeutics for diabetic nephropathy.

de Haan JB - Diabetes (2011)

View Article: PubMed Central - PubMed

Affiliation: Diabetic Complications Division, Oxidative Stress Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia. judy.dehaan@bakeridi.edu.au

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Diabetes is the major cause of chronic kidney disease worldwide with treatment options focused primarily on glucose control, blood pressure, lipid lowering, and the blockade of the renin-angiotensin system... One approach that is attracting attention is the use of compounds to bolster the natural cytoprotective responses of the body... The transcription factor NF-E2–related factor 2 (Nrf2), together with its negative regulator, Kelch-like ECH-associated protein 1 (Keap1), is considered one of the most important cellular defense mechanisms to combat oxidative stress with a particular role in the regulation of phase II detoxifying enzymes (Fig. 1)... In particular, NADPH quinone oxidoreductase, glutathione S-transferase, heme oxygenase-1, and γ-glutamylcysteine synthetase are well-studied targets of Nrf2 that are upregulated through the antioxidant response element found in the promoters of these genes... It is therefore not surprising that attention has focused on identifying small molecule activators of the Nrf2/Keap1 pathway... Many chemically diverse activators have already been identified, including the glutathione peroxidase-1 mimetic ebselen, sulforaphane found in cruciferous vegetables, caffeic acid phenethylester from the bee product propolis, cinnamic aldehyde (found in cinnamon bark), and most recently, bardoxolone methyl... A preclinical study by Zheng et al. published in this edition of Diabetes also demonstrates the potential utility of the Nrf2 agonists, sulforaphane and cinnamic aldehyde, for improving the metabolic profile and reducing renal injury in mice with streptozotocin-induced diabetes... Specifically, this treatment was associated with reduced oxidative stress and attenuated induction of the profibrotic mediator transforming growth factor-β, the growth inhibitory protein p21, and extracellular matrix proteins in the diabetic kidney... Importantly, sulforaphane and cinnamic aldehyde failed to protect against renal injury in diabetic Nrf2 knockout mice, suggesting that their renoprotective actions are specifically mediated via activation of Nrf2... Rather than directly targeting Nrf2, many agonists appear to work by suppressing its endogenous inhibitor, Keap1... Indeed, the study by Zheng et al. showed that the specific silencing of Keap1 using small interfering RNA was able to reduce the expression of transforming growth factor-β and matrix proteins in human renal mesangial cells under both normal and high glucose conditions... Beyond actions on renal fibrosis, small molecule activators of Nrf2 may also have direct actions on renal function.

Show MeSH

Related in: MedlinePlus

Upregulation of phase II detoxifying enzymes by small molecule activators involves activation of the Nrf2-Keap1 pathway. The transcription factor Nrf2 is held in an inactive state in the cytoplasm through its interaction with two molecules of its inhibitory partner, Keap1. Small molecule activators such as ebselen, sulforaphane, and bardoxolone interact with cysteine residues within Keap1 causing its dissociation from Nrf2. Specificity of a class of activator is thought to reside in the cysteine (cys) residue it interacts with. Unbound Nrf2 then translocates into the nucleus where it interacts with antioxidant response elements (AREs) of more than 300 genes. Upregulation of these phase II detoxification enzymes protects the cell against oxidative stress. Identification of clinically relevant small molecule activators of Nrf2 is offering promise as a new avenue for treatment against diseases such as diabetic nephropathy. (Adapted from Jung and Kwak [17].)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3198074&req=5

Figure 1: Upregulation of phase II detoxifying enzymes by small molecule activators involves activation of the Nrf2-Keap1 pathway. The transcription factor Nrf2 is held in an inactive state in the cytoplasm through its interaction with two molecules of its inhibitory partner, Keap1. Small molecule activators such as ebselen, sulforaphane, and bardoxolone interact with cysteine residues within Keap1 causing its dissociation from Nrf2. Specificity of a class of activator is thought to reside in the cysteine (cys) residue it interacts with. Unbound Nrf2 then translocates into the nucleus where it interacts with antioxidant response elements (AREs) of more than 300 genes. Upregulation of these phase II detoxification enzymes protects the cell against oxidative stress. Identification of clinically relevant small molecule activators of Nrf2 is offering promise as a new avenue for treatment against diseases such as diabetic nephropathy. (Adapted from Jung and Kwak [17].)

Mentions: One approach that is attracting attention is the use of compounds to bolster the natural cytoprotective responses of the body. The transcription factor NF-E2–related factor 2 (Nrf2), together with its negative regulator, Kelch-like ECH-associated protein 1 (Keap1), is considered one of the most important cellular defense mechanisms to combat oxidative stress (4) with a particular role in the regulation of phase II detoxifying enzymes (Fig. 1). In particular, NADPH quinone oxidoreductase, glutathione S-transferase, heme oxygenase-1, and γ-glutamylcysteine synthetase are well-studied targets of Nrf2 that are upregulated through the antioxidant response element found in the promoters of these genes (5). Therefore, the coordinated upregulation of genes coding for detoxification, antioxidant, and anti-inflammatory regulators is seen as a potential therapeutic strategy to protect against insults such as inflammation and oxidative stress that are known to be enhanced by the diabetic milieu.


Nrf2 activators as attractive therapeutics for diabetic nephropathy.

de Haan JB - Diabetes (2011)

Upregulation of phase II detoxifying enzymes by small molecule activators involves activation of the Nrf2-Keap1 pathway. The transcription factor Nrf2 is held in an inactive state in the cytoplasm through its interaction with two molecules of its inhibitory partner, Keap1. Small molecule activators such as ebselen, sulforaphane, and bardoxolone interact with cysteine residues within Keap1 causing its dissociation from Nrf2. Specificity of a class of activator is thought to reside in the cysteine (cys) residue it interacts with. Unbound Nrf2 then translocates into the nucleus where it interacts with antioxidant response elements (AREs) of more than 300 genes. Upregulation of these phase II detoxification enzymes protects the cell against oxidative stress. Identification of clinically relevant small molecule activators of Nrf2 is offering promise as a new avenue for treatment against diseases such as diabetic nephropathy. (Adapted from Jung and Kwak [17].)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198074&req=5

Figure 1: Upregulation of phase II detoxifying enzymes by small molecule activators involves activation of the Nrf2-Keap1 pathway. The transcription factor Nrf2 is held in an inactive state in the cytoplasm through its interaction with two molecules of its inhibitory partner, Keap1. Small molecule activators such as ebselen, sulforaphane, and bardoxolone interact with cysteine residues within Keap1 causing its dissociation from Nrf2. Specificity of a class of activator is thought to reside in the cysteine (cys) residue it interacts with. Unbound Nrf2 then translocates into the nucleus where it interacts with antioxidant response elements (AREs) of more than 300 genes. Upregulation of these phase II detoxification enzymes protects the cell against oxidative stress. Identification of clinically relevant small molecule activators of Nrf2 is offering promise as a new avenue for treatment against diseases such as diabetic nephropathy. (Adapted from Jung and Kwak [17].)
Mentions: One approach that is attracting attention is the use of compounds to bolster the natural cytoprotective responses of the body. The transcription factor NF-E2–related factor 2 (Nrf2), together with its negative regulator, Kelch-like ECH-associated protein 1 (Keap1), is considered one of the most important cellular defense mechanisms to combat oxidative stress (4) with a particular role in the regulation of phase II detoxifying enzymes (Fig. 1). In particular, NADPH quinone oxidoreductase, glutathione S-transferase, heme oxygenase-1, and γ-glutamylcysteine synthetase are well-studied targets of Nrf2 that are upregulated through the antioxidant response element found in the promoters of these genes (5). Therefore, the coordinated upregulation of genes coding for detoxification, antioxidant, and anti-inflammatory regulators is seen as a potential therapeutic strategy to protect against insults such as inflammation and oxidative stress that are known to be enhanced by the diabetic milieu.

View Article: PubMed Central - PubMed

Affiliation: Diabetic Complications Division, Oxidative Stress Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia. judy.dehaan@bakeridi.edu.au

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Diabetes is the major cause of chronic kidney disease worldwide with treatment options focused primarily on glucose control, blood pressure, lipid lowering, and the blockade of the renin-angiotensin system... One approach that is attracting attention is the use of compounds to bolster the natural cytoprotective responses of the body... The transcription factor NF-E2–related factor 2 (Nrf2), together with its negative regulator, Kelch-like ECH-associated protein 1 (Keap1), is considered one of the most important cellular defense mechanisms to combat oxidative stress with a particular role in the regulation of phase II detoxifying enzymes (Fig. 1)... In particular, NADPH quinone oxidoreductase, glutathione S-transferase, heme oxygenase-1, and γ-glutamylcysteine synthetase are well-studied targets of Nrf2 that are upregulated through the antioxidant response element found in the promoters of these genes... It is therefore not surprising that attention has focused on identifying small molecule activators of the Nrf2/Keap1 pathway... Many chemically diverse activators have already been identified, including the glutathione peroxidase-1 mimetic ebselen, sulforaphane found in cruciferous vegetables, caffeic acid phenethylester from the bee product propolis, cinnamic aldehyde (found in cinnamon bark), and most recently, bardoxolone methyl... A preclinical study by Zheng et al. published in this edition of Diabetes also demonstrates the potential utility of the Nrf2 agonists, sulforaphane and cinnamic aldehyde, for improving the metabolic profile and reducing renal injury in mice with streptozotocin-induced diabetes... Specifically, this treatment was associated with reduced oxidative stress and attenuated induction of the profibrotic mediator transforming growth factor-β, the growth inhibitory protein p21, and extracellular matrix proteins in the diabetic kidney... Importantly, sulforaphane and cinnamic aldehyde failed to protect against renal injury in diabetic Nrf2 knockout mice, suggesting that their renoprotective actions are specifically mediated via activation of Nrf2... Rather than directly targeting Nrf2, many agonists appear to work by suppressing its endogenous inhibitor, Keap1... Indeed, the study by Zheng et al. showed that the specific silencing of Keap1 using small interfering RNA was able to reduce the expression of transforming growth factor-β and matrix proteins in human renal mesangial cells under both normal and high glucose conditions... Beyond actions on renal fibrosis, small molecule activators of Nrf2 may also have direct actions on renal function.

Show MeSH
Related in: MedlinePlus