Aldose Reductase Inhibitor Protects against Hyperglycemic Stress by Activating Nrf2-Dependent Antioxidant Proteins

We have shown earlier that pretreatment of cultured cells with aldose reductase (ar) inhibitors prevents hyperglycemia-induced mitogenic and proinflammatory responses. however,the effects of ar inhibitors on nrf2-mediated anti-inflammatory responses have not been elucidated yet. we have investigated how ar inhibitor fidarestat protects high glucose-(hg-) induced cell viability changes by increasing the expression of nrf2 and its dependent phase ii antioxidant enzymes. fidarestat pretreatment prevents hg (25 mm)-induced thp1 monocyte viability. further,treatment of thp1 monocytes with fidarestat caused a time-dependent increase in the expression as well as the dna-binding activity of nrf2. in addition,fidarestat augmented the hg-induced nrf2 expression and activity and also upregulated the expression of nrf2-dependent proteins such as hemeoxygenase-1 (ho1) and nqo1 in thp1 cells. similarly,treatment with ar inhibitor also induced the expression of nrf2 and ho1 in stz-induced diabetic mice heart and kidney tissues. further,ar inhibition increased the hg-induced expression of antioxidant enzymes such as sod and catalase and activation of ampk-α1 in thp1 cells. our results thus suggest that pretreatment with ar inhibitor prepares the monocytes against hyperglycemic stress by overexpressing the nrf2-dependent antioxidative proteins. © 2017 kirtikar shukla et al.