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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

SF or CA alleviates renal damage induced in the STZ-diabetic model. A: Kidney-to-body weight ratios are provided. STZ injection increased weight ratios in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals, which could be significantly reduced by SF and CA treatment in Nrf2+/+ only. B and C: Albuminuria is reported as measures of UAE (B) and UACR (C). STZ injection increased UAE and UACR in both Nrf2+/+ (top panels) and Nrf2−/− (bottom panels) animals, which were significantly reduced by SF and CA treatment in Nrf2+/+ only. Kidney tissue sections from each mouse were subjected to HE, PAS, and trichrome staining. D: A representative image from one mouse per group is shown. E: PAS-stained tissues were used for semiquantitative scoring to get glomerulosclerotic index. A total of 30 glomeruli were scored for each mouse, and average scores with SD were shown (n = 3 per group). F: Electron microscopy of the GBM is displayed. GBM thickness was measured at 50 different sites (per animal) of the GBM in Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals and expressed as mean ± SD (n = 3 per group). Data in A–C 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 2: SF or CA alleviates renal damage induced in the STZ-diabetic model. A: Kidney-to-body weight ratios are provided. STZ injection increased weight ratios in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals, which could be significantly reduced by SF and CA treatment in Nrf2+/+ only. B and C: Albuminuria is reported as measures of UAE (B) and UACR (C). STZ injection increased UAE and UACR in both Nrf2+/+ (top panels) and Nrf2−/− (bottom panels) animals, which were significantly reduced by SF and CA treatment in Nrf2+/+ only. Kidney tissue sections from each mouse were subjected to HE, PAS, and trichrome staining. D: A representative image from one mouse per group is shown. E: PAS-stained tissues were used for semiquantitative scoring to get glomerulosclerotic index. A total of 30 glomeruli were scored for each mouse, and average scores with SD were shown (n = 3 per group). F: Electron microscopy of the GBM is displayed. GBM thickness was measured at 50 different sites (per animal) of the GBM in Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals and expressed as mean ± SD (n = 3 per group). Data in A–C 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: To investigate the therapeutic effects of Nrf2 activation on improvement of kidney performance in the STZ diabetic model, functional and pathological changes of the kidney were measured. The ratio of kidney weight-to-body weight was higher in all STZ-injected groups compared with untreated, which was significantly attenuated by treatment with SF or CA in Nrf2+/+ mice (Fig. 2A). Next, as indices of albuminuria, both urinary albumin excretion (UAE) and the urine albumin-to-creatinine ratio (UACR) were determined at 0, 10, and 18 weeks. Injection with STZ increased UAE and UACR in all treated groups; however, this increase was blunted by SF or CA treatment in Nrf2+/+ mice but not Nrf2−/− mice (Fig. 2B and C). These results demonstrate that SF or CA is able to improve albuminuria in Nrf2+/+ diabetic mice.


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)

SF or CA alleviates renal damage induced in the STZ-diabetic model. A: Kidney-to-body weight ratios are provided. STZ injection increased weight ratios in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals, which could be significantly reduced by SF and CA treatment in Nrf2+/+ only. B and C: Albuminuria is reported as measures of UAE (B) and UACR (C). STZ injection increased UAE and UACR in both Nrf2+/+ (top panels) and Nrf2−/− (bottom panels) animals, which were significantly reduced by SF and CA treatment in Nrf2+/+ only. Kidney tissue sections from each mouse were subjected to HE, PAS, and trichrome staining. D: A representative image from one mouse per group is shown. E: PAS-stained tissues were used for semiquantitative scoring to get glomerulosclerotic index. A total of 30 glomeruli were scored for each mouse, and average scores with SD were shown (n = 3 per group). F: Electron microscopy of the GBM is displayed. GBM thickness was measured at 50 different sites (per animal) of the GBM in Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals and expressed as mean ± SD (n = 3 per group). Data in A–C 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 2: SF or CA alleviates renal damage induced in the STZ-diabetic model. A: Kidney-to-body weight ratios are provided. STZ injection increased weight ratios in both Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals, which could be significantly reduced by SF and CA treatment in Nrf2+/+ only. B and C: Albuminuria is reported as measures of UAE (B) and UACR (C). STZ injection increased UAE and UACR in both Nrf2+/+ (top panels) and Nrf2−/− (bottom panels) animals, which were significantly reduced by SF and CA treatment in Nrf2+/+ only. Kidney tissue sections from each mouse were subjected to HE, PAS, and trichrome staining. D: A representative image from one mouse per group is shown. E: PAS-stained tissues were used for semiquantitative scoring to get glomerulosclerotic index. A total of 30 glomeruli were scored for each mouse, and average scores with SD were shown (n = 3 per group). F: Electron microscopy of the GBM is displayed. GBM thickness was measured at 50 different sites (per animal) of the GBM in Nrf2+/+ (top panel) and Nrf2−/− (bottom panel) animals and expressed as mean ± SD (n = 3 per group). Data in A–C 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: To investigate the therapeutic effects of Nrf2 activation on improvement of kidney performance in the STZ diabetic model, functional and pathological changes of the kidney were measured. The ratio of kidney weight-to-body weight was higher in all STZ-injected groups compared with untreated, which was significantly attenuated by treatment with SF or CA in Nrf2+/+ mice (Fig. 2A). Next, as indices of albuminuria, both urinary albumin excretion (UAE) and the urine albumin-to-creatinine ratio (UACR) were determined at 0, 10, and 18 weeks. Injection with STZ increased UAE and UACR in all treated groups; however, this increase was blunted by SF or CA treatment in Nrf2+/+ mice but not Nrf2−/− mice (Fig. 2B and C). These results demonstrate that SF or CA is able to improve albuminuria in Nrf2+/+ diabetic mice.

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