We have recently demonstrated that aldose reductase (AR), an enzyme that catalyzes the reduction of reactive oxygen species-induced lipid aldehydes and their glutathione (GSH)- conjugates (GS-LDAs), is the main mediator of oxidative and inflammatory signals induced by hyperglycemia, growth factors and cytokines. Our studies from previously funded merit award have shown that inhibition of AR prevents the high glucose-induced vascular cells growth and activation of NF-KB signalosome and expression of NF-kB- dependent inflammatory markers. We have also shown that inhibition of AR prevents hyperglycemia - induced inflammatory signaling in diabetic mice. Although, we have identified that AR-catalyzed reduced product, GS-DHN mediates NF-kB-dependent inflammatory markers by activating signals downstream to protein kinase C (PKC), the molecular mechanisms that regulate cellular redox homeostasis leading to immune response are not clearly understood. We hypothesize that glutathione conjugates of LDAs are endogenous danger signals that activate NALP3 inflammasome leading to increased cytokine production and inflammation that contribute to vascular complications in diabetes. Our goal is to investigate the mechanisms by which AR catalytic activity plays a critical role in redox regulation of inflammatory mediators which propagate molecular pathways such as endothelial dysfunction and neointimal formation in mouse models of diabetes. Our long-term goal is to understand the molecular mechanism(s) by which the reduction of LDAs and their glutathione conjugates by AR regulates inflammatory signaling that contributes to diabetic vascular complications. By using specific cultured cells and in vivo WT, AR, NALP3, IL-1b and caspase-1 null mouse models of streptozotocin-induced diabetes, we will examine how AR-catalyzed GS-LDAs regulate the hyperglycemia -induced innate immune response that causes endothelial dysfunction and neointimal hyperplasia.
Our specific aims are to 1) elucidate the molecular mechanisms by which catalysis of LDAs by AR regulates NF-kB-dependent pro-inflammatory and Nrf-2-dependent anti-inflammatory pathways in hyperglycaemia, 2) examine the signaling events by which LDAs and their GSH conjugates act as endogenous danger signals, and 3) delineate the contribution of AR-generated GS-LDA to the activation of NALP3 inflammasome that induces endothelial dysfunction and promotes neointimal hyperplasia in diabetes. Completion of the proposed studies will identify the molecular mechanisms by which AR regulates cellular redox homeostasis, immune response and vascular inflammation. These studies will also lay the foundation for the use of AR inhibition by specific inhibitor, fidarestat that has already undergon phase-iii clinical trials for diabetic neuropathy and found to be safe, as a novel anti-inflammator approach in the prevention and treatment of diabetic cardiovascular complications.

Public Health Relevance

Cardiovascular diseases are the leading cause of mortality in patients with diabetes. We will use cell culture and animal models in our investigations to better understand how aldose reductase-regulated lipid metabolism mediates inflammasome-triggered innate immune response that contributes to the diabetes-induced vascular injury. The results from this study will be potentially important in developing new therapies to prevent death of patients with diabetic vascular complications.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Jones, Teresa L Z
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University of Texas Medical Br Galveston
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United States
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Saxena, Ashish; Tammali, Ravinder; Ramana, Kota V et al. (2018) Aldose Reductase Inhibitor, Fidarestat Prevents High-fat Diet-induced Intestinal Polyps in ApcMin/+ Mice. Curr Cancer Drug Targets 18:905-911
Sonowal, Himangshu; Pal, Pabitra; Shukla, Kirtikar et al. (2018) Aldose reductase inhibitor, fidarestat prevents doxorubicin-induced endothelial cell death and dysfunction. Biochem Pharmacol 150:181-190
Shukla, Kirtikar; Sonowal, Himangshu; Saxena, Ashish et al. (2018) Didymin prevents hyperglycemia-induced human umbilical endothelial cells dysfunction and death. Biochem Pharmacol 152:1-10
Shukla, Kirtikar; Pal, Pabitra Bikash; Sonowal, Himangshu et al. (2017) Aldose Reductase Inhibitor Protects against Hyperglycemic Stress by Activating Nrf2-Dependent Antioxidant Proteins. J Diabetes Res 2017:6785852
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Pal, Pabitra B; Sonowal, Himangshu; Shukla, Kirtikar et al. (2017) Aldose Reductase Mediates NLRP3 Inflammasome-Initiated Innate Immune Response in Hyperglycemia-Induced Thp1 Monocytes and Male Mice. Endocrinology 158:3661-3675