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.
Highlights
To date, diabetes-associated complications, especially cardiovascular and chronic renal diseases, remain a tremendous threat to a diabetic patient’s survival and quality of life despite the use of currently available therapies
The prevention of oxidative stress and inflammation can be achieved through activating the nuclear factor E2-related factor 2 (Nrf2)/antioxidant-response element (ARE)2 signaling pathway, which is known to play a pivotal role in the up-regulation of cellular antioxidant enzymes such as heme oxygenase-1 (HO-1), glutathione peroxidase-1 (GPx-1), and NAD(P)H dehydrogenase 1 (NQO-1) [3, 4]
These findings suggested that Salvianolic acid A (SAA) treatment in combination with MET was helpful in further improving high glucose (HG)-induced injury, which partially supported our in vivo results
Summary
General Parameters of Diabetic Mice—Compared with nondiabetic mice, all diabetic mice showed significantly decreased body weights with significantly increased food and water intake regardless of treatment. Left and right kidney indices revealed a trend toward a significant increase in diabetic mice This trend was mitigated after treatment with MET or SAA in combination with MET. MET therapy had no effect on DHE fluorescence in the diabetic kidney (see Fig. 5, A and D) These data suggested that SAA, and not MET, significantly attenuated oxidative stress in STZ-induced diabetic mice with SAA treatment or a combination. Consistent with the reported findings that activation of AMPK or the Nrf2/ARE pathway reduced HG-induced harmful effects in several types of cells (34 –36), our results showed that treatment with SAA, MET, and their combination reduced increased expression of NF-B p65 and ␣-SMA in HG-exposed HK-2 cells, with the biggest decrease observed in SAA treatment in combination with MET (Fig. 7D). HG-induced ROS in HK-2 cells, which was assessed by DHE and 2Ј,7Јdichlorofluorescin diacetate (DCFH-DA), was significantly
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