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Effects of the Nrf2 Protein Modulator Salvianolic Acid A Alone or Combined with Metformin on Diabetes-associated Macrovascular and Renal Injury
- Source :
- The Journal of biological chemistry. 291(42)
- Publication Year :
- 2015
-
Abstract
- Nuclear factor E2-related factor 2 (Nrf2) is considered a promising target against diabetic complications such as cardiovascular diseases and diabetic nephropathy. Herein, we investigated the effects of a potential Nrf2 modulator, salvianolic acid A (SAA), which is a natural polyphenol, on diabetes-associated macrovascular and renal injuries in streptozotocin-induced diabetic mice. Given that lowering glucose is the first objective of diabetic patients, we also examined the effects of SAA combined with metformin (MET) on both complications. Our results showed that SAA significantly increased the macrovascular relaxation response to acetylcholine and sodium nitroprusside in diabetic mice. Interestingly, treatment with SAA alone only provided minor protection against renal injury, as reflected by minor improvements in impaired renal function and structure, despite significantly reduced oxidative stress observed in the diabetic kidney. We demonstrated that decreased oxidative stress and NF-κB p65 expression were associated with SAA-induced expression of Nrf2-responsive antioxidant enzymes heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase (quinone) 1 (NQO-1), and glutathione peroxidase-1 (GPx-1) in vivo or in vitro, which suggested that SAA was a potential Nrf2 modulator. More significantly, compared with treatment with either SAA or MET alone, we found that their combination provided further protection against the macrovascular and renal injury, which was at least partly due to therapeutic activation of both MET-mediated AMP-activated protein kinase and SAA-mediated Nrf2/antioxidant-response element pathways. These findings suggested that polyphenol Nrf2 modulators, especially combined with drugs activating AMP-activated protein kinase, including hypoglycemic drugs, are worthy of further investigation to combat diabetic complications.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
NF-E2-Related Factor 2
Diabetic angiopathy
Alkenes
medicine.disease_cause
Biochemistry
Diabetes Mellitus, Experimental
Diabetic nephropathy
03 medical and health sciences
Mice
Glutathione Peroxidase GPX1
In vivo
Internal medicine
Diabetes mellitus
medicine
NAD(P)H Dehydrogenase (Quinone)
Animals
Diabetic Nephropathies
Molecular Biology
chemistry.chemical_classification
Glutathione Peroxidase
Mice, Inbred ICR
Chemistry
Glutathione peroxidase
Membrane Proteins
Polyphenols
Cell Biology
medicine.disease
Metformin
030104 developmental biology
Endocrinology
Metabolism
Sodium nitroprusside
Oxidative stress
Diabetic Angiopathies
Heme Oxygenase-1
medicine.drug
Subjects
Details
- ISSN :
- 1083351X
- Volume :
- 291
- Issue :
- 42
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....94d400dc0f2ad6ee2af0566553aaa660