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

• Published in: Journal of Diabetes Research Vol. 2017; no. 2017; pp. 1 - 9
• Main Authors: Srivastava, Satish K., Sonowal, Himangshu, Pal, Pabitra Bikash, Shukla, Kirtikar, Ramana, Kota V.
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Publishing Corporation 01.01.2017; Hindawi; John Wiley & Sons, Inc; Hindawi Limited
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Aldose reductase; Animals; Antibodies; Antioxidants; Apoptosis; Catalase - metabolism; Cell Survival - drug effects; Control; Cytokines; Deoxyribonucleic acid; Diabetes; Diabetes Mellitus, Experimental - metabolism; DNA; Enzyme Inhibitors - pharmacology; Enzymes; Gene expression; Glucose; Health aspects; Heart - drug effects; Heme Oxygenase-1 - metabolism; Hyperglycemia; Hyperglycemia - metabolism; Imidazolidines - pharmacology; Kidney - drug effects; Kidney - metabolism; Membrane Proteins - metabolism; Mice; Monocytes - drug effects; Monocytes - metabolism; Myocardium - metabolism; NF-E2-Related Factor 2 - metabolism; Oxidative stress; Oxidative Stress - drug effects; Penicillin; Proteins; Signal Transduction - drug effects; Superoxide Dismutase - metabolism; Transcription factors; United States > US
• ISSN: 2314-6745; 2314-6753
• DOI: 10.1155/2017/6785852

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.