Cellular death, reactive oxygen species (ROS) and diabetic complications

Abstract

Chronic or intermittent hyperglycemia is associated with the development of diabetic complications. Several signaling pathways can be altered by having hyperglycemia in different tissues, producing oxidative stress, the formation of advanced glycation end products (AGEs), as well as the secretion of the pro-inflammatory cytokines and cellular death (pathological autophagy and/or apoptosis). However, the signaling pathways that are directly triggered by hyperglycemia appear to have a pivotal role in diabetic complications due to the production of reactive oxygen species (ROS), oxidative stress, and cellular death. The present review will discuss the role of cellular death in diabetic complications, and it will suggest the cause and the consequences between the hyperglycemia-induced signaling pathways and cell death. The signaling pathways discussed in this review are to be described step-by-step, together with their respective inhibitors. They involve diacylglycerol, the activation of protein kinase C (PKC) and NADPH-oxidase system, and the consequent production of ROS. This was initially entitled the "dangerous metabolic route in diabetes". The historical usages and the recent advancement of new drugs in controlling possible therapeutical targets have been highlighted, in order to evaluate the evolution of knowledge in this sensitive area. It has recently been shown that the metabolic responses to stimuli (i.e., hyperglycemia) involve an integrated network of signaling pathways, in order to define the exact responses. Certain new drugs have been experimentally tested-or suggested and proposed-for their ability to modulate the possible biochemical therapeutical targets for the downregulation of retinopathy, nephropathy, neuropathy, heart disease, angiogenesis, oxidative stress, and cellular death. The aim of this study was to critically and didactically evaluate the exact steps of these signaling pathways and hence mark the indicated sites for the actions of such drugs and their possible consequences. This review will emphasize, besides others, the therapeutical targets for controlling the signaling pathways, when aimed at the downregulation of ROS generation, oxidative stress, and, consequently, cellular death-with all of these conditions being a problem in diabetes.

Fig. 1. Oxidative stress and cell death: necroptosis, a programmed necrosis of inflammatory cell, and apoptosis can be induced in diabetes by AGEs, ROS, and MGO, leading to diabetes complications (retinopathy, age-related macular etc.)

MGO = methylglyoxal, AGEs = advanced glycation end products, ROS = reactive oxygen species.

Fig. 2. Balance between autophagy and apoptosis: apoptosis is downregulated by autophagy

The activation of mTORC1 depends on PKC, which is activated by DAG. Thus, PKC in conjunction with ROS and mTORC1 pathway are associated in the control of cellular autophagy. Akt/mammalian target of rapamycin complex 1 = mTORC1, ROS reactive oxygen species, PKC = protein kinase C, DAG = diacylglycerol.

Fig. 3. Targets for modulation of cell death: some points may act as modulators of cell death depending on the kind of activation

Apoptosis induced by TLR activation has been suggested to be downregulated by silencing of TLR4 gene in experimental model or using soluble RAGE and/or specific antibodies against RAGE. Cell death is a source of HMGB-1, an activator of RAGE. TLR TLR-Toll-like receptors, RAGE receptor for advanced glycation end products.

Fig. 4. Proposed signaling pathways from hyperglycemia to ROS production and cytokine release leading to diabetes complications

Hyperglycemia increases diacylglycerol (DAG) content by the activation of phospholipase C or D, which activates protein kinase C (PKC). PKC activates NADPH oxidase. NADPH oxidase complex consists of the cytosolic components p47phox, p67phox, p40phox, and a low-molecular-weight G-protein, Rac 1 or Rac 2, and the membrane-associated NOX2 and p22phox. Activation of the enzyme complex requires translocation of the cytosolic components to the plasma membrane, and their association to NOX2, produces reactive oxygen species (ROS). AGE-RAGE, FFA-TLR, and oxLDL-TLR activate downstream IKK (IkappaB kinases) pathways, and PKC. IKK phosphorylates IkappaB (inhibitor of kappa light chain gene enhancer in B cells), leading to translocation of the transcription factor NF-kappaB to the nucleus to control the expression of pro-inflammatory cytokines. ⊥ points of inhibition. 1 Inhibition of diacylglerol kinase; 2 Inhibition of PKC; 3 Inhibition of NADPH oxidase. AGE advanced glycation end products, DAG diacylglycerol, DAGK diacylicerol kinase, FFA free fatty acid, GPR G-protein-coupled receptors, IKK IkappaB kinases, IP3 inositol trisphosphate, LDL low density lipoprotein, NF-kappaB nuclear factor, oxLDL oxidized low density lipoprotein, PIP2 phosphatidylinositol-4,5-bisphosphate, PKC protein kinase C, PLC phospholipase, PLD phospholipase D, RAGE receptor for advanced glycation end products, ROS reactive oxygen species, TCA triacylglycerol, TLR Toll-like receptor.