Effects of the Nrf2 Protein Modulator Salvianolic Acid A Alone or Combined with Metformin on Diabetes-associated Macrovascular and Renal Injury

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.

Salvianolic Acid A Protects Against Diabetic Nephropathy through Ameliorating Glomerular Endothelial Dysfunction via Inhibiting AGE-RAGE Signaling

“…GV was calculated as GV = β / κ × (GA)3/2, where β = 1.38, which is the shape coefficient for spheres (the idealized shape of glomeruli), and κ = 1.1, which is a size distribution coefficient. HE staining was conducted and renal interstitial inflammation was scored as previously reported [26]. Briefly, inflammation was scored on a range of 0 to 3.…”

The Effect of Nrf2 on Diabetic Complications

“…Wu et al [8] have demonstrated that in addition to upreg-ulating Nrf2 by increasing miR-200a, C66 also protects against DN by inhibiting miR-21.…”

“…The antioxidant response provided by the NFE2L2 and Keap1-NFE2L2/ARE signaling pathways protects the pulmonary, hepatic, digestive, neural and cardiovascular systems, and Nrf2 is considered a promising target against diabetic complications such as cardiovascular diseases and diabetic nephropathy [7][8][9].…”

“…Research has revealed that the expressions of Nrf2-mediated anti-oxidative enzymes, including HO-1, NQO-1, and GPx-1, were signiicantly increased in the diabetic kidney when treated with salvianolic acid A (SAA) alone or in combination with metformin (MET). SAA is a polyphenol derivative extracted from the root of Salvia miltiorrhiza, which is known to show a variety of pharmacological activities including antioxidant, anti-inlammatory, and antiplatelet properties [8,9].…”

“…The MET is an oral hypoglycemic agent, which is widely used in patients with type 2 diabetes. MET decreases blood glucose levels by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization [8][9][10].…”