Therapeutic Potential of Nrf2 Activators in Streptozotocin-Induced Diabetic Nephropathy
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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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Cinnamaldehyde suppresses oxidative stress in kidney diseases.
“Flavonoid quercetin alleviates oxidative stress in diabetic nephropathy (Tong et al. 2017), natural alkaloid berberine can inhibit the progression of the disease [Wu et al. 2012), and naturally occurring cinnamaldehyde is able to suppress oxidative stress in kidney diseases (Zheng et al. 2011).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Zheng et al. 2011
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Self-citation
- Authors
- Zheng, H., Whitman, S. A., Wu, W., Wondrak, G. T., Wong, P. K., Fang, D., & Zhang, D. D.
- Affiliations
- University of Arizona (US)
- Northwestern University (US)
- Corresponding author
- Zhang, Donna D.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2011-10-17
- Volume
- 60
- Issue
- 11
- Pages
- 3055-3066
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3198067
- OpenAlex
- W2154111720
- Cited by
- 507
- References
- 46
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 26 · 2023: 26 · 2022: 40 · 2021: 45 · 2020: 49 · 2019: 41 · 2018: 38 · 2017: 51 · 2016: 34 · 2015: 45 · 2014: 29 · 2013: 34 · 2012: 20
- FWCI
- 10.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- University of Arizona Cancer Center
- National Natural Science Foundation of China
- National Institute of Environmental Health Sciences (R01ES015010, T32ES007091, P30ES006694, (ES015010)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Keywords
- Nrf2 activation, diabetic nephropathy, streptozotocin-induced diabetes, sulforaphane, cinnamaldehyde, dietary compounds, oxidative stress, glomerular injury, TGF-β1, extracellular matrix, p21, renal mesangial cells, renal fibrosis, hyperglycemia, renal function
- MeSH terms
- Acrolein, Animals, Cells, Cultured, Diabetic Nephropathies, Dose-Response Relationship, Drug, Humans, Kidney, Mice, Inbred C57BL, Random Allocation, Sulfoxides, Thiocyanates, Extracellular Matrix Proteins, Reactive Oxygen Species, Isothiocyanates, Mice, Knockout, Oxidative Stress, RNA Interference, RNA, Small Interfering, Cell Proliferation, Mesangial Cells, Cyclin-Dependent Kinase Inhibitor p21, NF-E2-Related Factor 2, Mice, Transforming Growth Factor beta1
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