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Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy.

Zheng H, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, Zhang DD - Diabetes (2011)

Bottom Line: Changes in protein expression of the Nrf2 pathway, as well as transforming growth factor-β1 (TGF-β1), fibronectin (FN), collagen IV, and p21/WAF1Cip1 (p21) were analyzed.Nrf2 activation reduced oxidative damage and suppressed the expression of TGF-β1, extracellular matrix proteins and p21 both in vivo and in HRMCs.In addition, Nrf2 activation reverted p21-mediated growth inhibition and hypertrophy of HRMCs under hyperglycemic conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, USA.

ABSTRACT

Objective: To determine whether dietary compounds targeting NFE2-related factor 2 (Nrf2) activation can be used to attenuate renal damage and preserve renal function during the course of streptozotocin (STZ)-induced diabetic nephropathy.

Research design and methods: Diabetes was induced in Nrf2(+/+) and Nrf2(-/-) mice by STZ injection. Sulforaphane (SF) or cinnamic aldehyde (CA) was administered 2 weeks after STZ injection and metabolic indices and renal structure and function were assessed (18 weeks). Markers of diabetes including blood glucose, insulin, polydipsia, polyuria, and weight loss were measured. Pathological alterations and oxidative damage in glomeruli were also determined. Changes in protein expression of the Nrf2 pathway, as well as transforming growth factor-β1 (TGF-β1), fibronectin (FN), collagen IV, and p21/WAF1Cip1 (p21) were analyzed. The molecular mechanisms of Nrf2-mediated protection were investigated in an in vitro model using human renal mesangial cells (HRMCs).

Results: SF or CA significantly attenuated common metabolic disorder symptoms associated with diabetes in Nrf2(+/+) but not in Nrf2(-/-) mice, indicating SF and CA function through specific activation of the Nrf2 pathway. Furthermore, SF or CA improved renal performance and minimized pathological alterations in the glomerulus of STZ-Nrf2(+/+) mice. Nrf2 activation reduced oxidative damage and suppressed the expression of TGF-β1, extracellular matrix proteins and p21 both in vivo and in HRMCs. In addition, Nrf2 activation reverted p21-mediated growth inhibition and hypertrophy of HRMCs under hyperglycemic conditions.

Conclusions: We provide experimental evidence indicating that dietary compounds targeting Nrf2 activation can be used therapeutically to improve metabolic disorder and relieve renal damage induced by diabetes.

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Related in: MedlinePlus

Activation of Nrf2 by SF or CA improves metabolic disorder in an STZ-induced diabetic model. A: The average level of blood glucose in each animal group is plotted. STZ animals (■) showed significant increase in blood glucose levels in both Nrf2+/+ (left panel) and Nrf2−/− animals (right panel). SF (♦) and CA (●,▲) treatment significantly reduced blood glucose in Nrf2+/+ only. B: Body weights of Nrf2+/+ (left panel) and Nrf2−/− (right panel) animals are displayed. STZ injection (■) caused significant decrease in weight in all animals that was recovered by SF (♦) and CA (●,▲) treatment in Nrf2+/+ only. C: Urine output from Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals is shown. STZ injection increased urine output in Nrf2+/+ animals (top panel) with a more significant increase in Nrf2−/− animals (bottom panel). SF and CA treatment significantly reduced urine output at 10 and 18 weeks in Nrf2+/+ only. D: Water consumption in the last 24 h before these mice were killed is reported. STZ injection increased water intake in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals. SF and CA treatment significantly reduced consumption in Nrf2+/+ only. E: Blood insulin is displayed. STZ injection decreased blood insulin levels in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals. SF and CA did not affect insulin levels in any animals. Data in A–E are expressed as mean ± SD (n = 8). *P < 0.05 compared with control. #P < 0.05 dietary treatment compared with STZ alone. (A high-quality color representation of this figure is available in the online issue.)
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Figure 1: Activation of Nrf2 by SF or CA improves metabolic disorder in an STZ-induced diabetic model. A: The average level of blood glucose in each animal group is plotted. STZ animals (■) showed significant increase in blood glucose levels in both Nrf2+/+ (left panel) and Nrf2−/− animals (right panel). SF (♦) and CA (●,▲) treatment significantly reduced blood glucose in Nrf2+/+ only. B: Body weights of Nrf2+/+ (left panel) and Nrf2−/− (right panel) animals are displayed. STZ injection (■) caused significant decrease in weight in all animals that was recovered by SF (♦) and CA (●,▲) treatment in Nrf2+/+ only. C: Urine output from Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals is shown. STZ injection increased urine output in Nrf2+/+ animals (top panel) with a more significant increase in Nrf2−/− animals (bottom panel). SF and CA treatment significantly reduced urine output at 10 and 18 weeks in Nrf2+/+ only. D: Water consumption in the last 24 h before these mice were killed is reported. STZ injection increased water intake in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals. SF and CA treatment significantly reduced consumption in Nrf2+/+ only. E: Blood insulin is displayed. STZ injection decreased blood insulin levels in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals. SF and CA did not affect insulin levels in any animals. Data in A–E are expressed as mean ± SD (n = 8). *P < 0.05 compared with control. #P < 0.05 dietary treatment compared with STZ alone. (A high-quality color representation of this figure is available in the online issue.)

Mentions: The effectiveness of dietary Nrf2 activators in alleviating metabolic disorder was assessed in the STZ-induced diabetic model in both Nrf2+/+ and Nrf2−/− mice, and common metabolic disorder indices associated with diabetes were measured. In response to STZ, mice showed significantly increased blood glucose levels (Fig. 1A), reduced weight gain (Fig. 1B), increased urine production (Fig. 1C), and increased water uptake (Fig. 1D). Importantly, treatment of diabetic animals with SF or CA significantly alleviated all indices of metabolic dysfunction in Nrf2+/+ animals only, demonstrating the Nrf2-dependent response to SF and CA. In addition, STZ injection decreased insulin levels significantly, which was unaltered by treatment with SF or CA regardless of genotype (Fig. 1E), indicating that the protective effects of SF and CA were not insulin dependent. Since treatment with Nrf2 activators began 2-weeks post-STZ injection, after the pancreatic β-cells had been destroyed and diabetes was established, we did not expect SF or CA treatments to influence circulating insulin levels in this study. Taken together, these results indicate that SF or CA treatment significantly attenuated metabolic disorder induced by STZ, and that this protective effect was independent of circulating insulin levels.


Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy.

Zheng H, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, Zhang DD - Diabetes (2011)

Activation of Nrf2 by SF or CA improves metabolic disorder in an STZ-induced diabetic model. A: The average level of blood glucose in each animal group is plotted. STZ animals (■) showed significant increase in blood glucose levels in both Nrf2+/+ (left panel) and Nrf2−/− animals (right panel). SF (♦) and CA (●,▲) treatment significantly reduced blood glucose in Nrf2+/+ only. B: Body weights of Nrf2+/+ (left panel) and Nrf2−/− (right panel) animals are displayed. STZ injection (■) caused significant decrease in weight in all animals that was recovered by SF (♦) and CA (●,▲) treatment in Nrf2+/+ only. C: Urine output from Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals is shown. STZ injection increased urine output in Nrf2+/+ animals (top panel) with a more significant increase in Nrf2−/− animals (bottom panel). SF and CA treatment significantly reduced urine output at 10 and 18 weeks in Nrf2+/+ only. D: Water consumption in the last 24 h before these mice were killed is reported. STZ injection increased water intake in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals. SF and CA treatment significantly reduced consumption in Nrf2+/+ only. E: Blood insulin is displayed. STZ injection decreased blood insulin levels in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals. SF and CA did not affect insulin levels in any animals. Data in A–E are expressed as mean ± SD (n = 8). *P < 0.05 compared with control. #P < 0.05 dietary treatment compared with STZ alone. (A high-quality color representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3198067&req=5

Figure 1: Activation of Nrf2 by SF or CA improves metabolic disorder in an STZ-induced diabetic model. A: The average level of blood glucose in each animal group is plotted. STZ animals (■) showed significant increase in blood glucose levels in both Nrf2+/+ (left panel) and Nrf2−/− animals (right panel). SF (♦) and CA (●,▲) treatment significantly reduced blood glucose in Nrf2+/+ only. B: Body weights of Nrf2+/+ (left panel) and Nrf2−/− (right panel) animals are displayed. STZ injection (■) caused significant decrease in weight in all animals that was recovered by SF (♦) and CA (●,▲) treatment in Nrf2+/+ only. C: Urine output from Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals is shown. STZ injection increased urine output in Nrf2+/+ animals (top panel) with a more significant increase in Nrf2−/− animals (bottom panel). SF and CA treatment significantly reduced urine output at 10 and 18 weeks in Nrf2+/+ only. D: Water consumption in the last 24 h before these mice were killed is reported. STZ injection increased water intake in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals. SF and CA treatment significantly reduced consumption in Nrf2+/+ only. E: Blood insulin is displayed. STZ injection decreased blood insulin levels in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals. SF and CA did not affect insulin levels in any animals. Data in A–E are expressed as mean ± SD (n = 8). *P < 0.05 compared with control. #P < 0.05 dietary treatment compared with STZ alone. (A high-quality color representation of this figure is available in the online issue.)
Mentions: The effectiveness of dietary Nrf2 activators in alleviating metabolic disorder was assessed in the STZ-induced diabetic model in both Nrf2+/+ and Nrf2−/− mice, and common metabolic disorder indices associated with diabetes were measured. In response to STZ, mice showed significantly increased blood glucose levels (Fig. 1A), reduced weight gain (Fig. 1B), increased urine production (Fig. 1C), and increased water uptake (Fig. 1D). Importantly, treatment of diabetic animals with SF or CA significantly alleviated all indices of metabolic dysfunction in Nrf2+/+ animals only, demonstrating the Nrf2-dependent response to SF and CA. In addition, STZ injection decreased insulin levels significantly, which was unaltered by treatment with SF or CA regardless of genotype (Fig. 1E), indicating that the protective effects of SF and CA were not insulin dependent. Since treatment with Nrf2 activators began 2-weeks post-STZ injection, after the pancreatic β-cells had been destroyed and diabetes was established, we did not expect SF or CA treatments to influence circulating insulin levels in this study. Taken together, these results indicate that SF or CA treatment significantly attenuated metabolic disorder induced by STZ, and that this protective effect was independent of circulating insulin levels.

Bottom Line: Changes in protein expression of the Nrf2 pathway, as well as transforming growth factor-β1 (TGF-β1), fibronectin (FN), collagen IV, and p21/WAF1Cip1 (p21) were analyzed.Nrf2 activation reduced oxidative damage and suppressed the expression of TGF-β1, extracellular matrix proteins and p21 both in vivo and in HRMCs.In addition, Nrf2 activation reverted p21-mediated growth inhibition and hypertrophy of HRMCs under hyperglycemic conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, USA.

ABSTRACT

Objective: To determine whether dietary compounds targeting NFE2-related factor 2 (Nrf2) activation can be used to attenuate renal damage and preserve renal function during the course of streptozotocin (STZ)-induced diabetic nephropathy.

Research design and methods: Diabetes was induced in Nrf2(+/+) and Nrf2(-/-) mice by STZ injection. Sulforaphane (SF) or cinnamic aldehyde (CA) was administered 2 weeks after STZ injection and metabolic indices and renal structure and function were assessed (18 weeks). Markers of diabetes including blood glucose, insulin, polydipsia, polyuria, and weight loss were measured. Pathological alterations and oxidative damage in glomeruli were also determined. Changes in protein expression of the Nrf2 pathway, as well as transforming growth factor-β1 (TGF-β1), fibronectin (FN), collagen IV, and p21/WAF1Cip1 (p21) were analyzed. The molecular mechanisms of Nrf2-mediated protection were investigated in an in vitro model using human renal mesangial cells (HRMCs).

Results: SF or CA significantly attenuated common metabolic disorder symptoms associated with diabetes in Nrf2(+/+) but not in Nrf2(-/-) mice, indicating SF and CA function through specific activation of the Nrf2 pathway. Furthermore, SF or CA improved renal performance and minimized pathological alterations in the glomerulus of STZ-Nrf2(+/+) mice. Nrf2 activation reduced oxidative damage and suppressed the expression of TGF-β1, extracellular matrix proteins and p21 both in vivo and in HRMCs. In addition, Nrf2 activation reverted p21-mediated growth inhibition and hypertrophy of HRMCs under hyperglycemic conditions.

Conclusions: We provide experimental evidence indicating that dietary compounds targeting Nrf2 activation can be used therapeutically to improve metabolic disorder and relieve renal damage induced by diabetes.

Show MeSH
Related in: MedlinePlus