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

Kirtikar Shukla,Himangshu Sonowal,Pabitra Bikash Pal,Satish K Srivastava,Kota V Ramana

doi:10.1155/2017/6785852

Kirtikar Shukla, Himangshu Sonowal + Show 3 more

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https://doi.org/10.1155/2017/6785852

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Abstract

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.

Highlights

Hyperglycemia is a major contributor to inflammation, apoptosis, profound vasodilation, tissue damage, and dysfunction in patients with diabetes mellitus [1]
We have demonstrated that fidarestat induces nuclear factor-erythroid-2-related factor 2 (Nrf2)-mediated antioxidative and antiinflammatory pathways in Thp1 monocytic cells
Fidarestat augmented the high glucose- (HG-)induced expression of Nrf2 and its downstream targets. These results suggest that preincubation with aldose reductase (AR) inhibitors prepares the cells to defend against pathological effects of hyperglycemia

Summary

Introduction

Hyperglycemia is a major contributor to inflammation, apoptosis, profound vasodilation, tissue damage, and dysfunction in patients with diabetes mellitus [1]. Our recent studies indicate that inhibition of the polyol pathway enzyme aldose reductase (AR) prevents cytokine- and hyperglycemia-induced increase in inflammatory markers in macrophages, vascular cells, and diabetic mice [3, 4] by preventing the activation of NFκB- and AP1-induced proinflammatory signals [3, 5]. We have shown that preincubation with AR inhibitor prevents hyperglycemia- and cytokine-induced proliferation of vascular cells and apoptosis of macrophages [6,7,8]. While these studies indicate that inhibition of AR could prevent oxidative stress-induced inflammatory response, the mechanism(s) by which inhibition of AR prepares the cells against oxidative stress is not known. It has been well established that activation of the Nrf pathway in response to oxidative stress protects the cells and tissues from oxidative injury [10]

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