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(2011) Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy Nat. Rev. Nephrol. doi:10.1038/nrneph.2011.51 PowerPoint Presentation: Oxidative stress in early diabetic nephropathy: fueling the fire Dhruv K. Singh, Peter Winocour & Ken Farrington Abstract Diabetic nephropathy is a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease worldwide. The treatment costs of diabetes mellitus and its complications represent a huge burden on health-care expenditures, creating a major need to identify modifiable factors concerned in the pathogenesis and progression of diabetic nephropathy. Chronic hyperglycemia remains the primary cause of the metabolic, biochemical and vascular abnormalities in diabetic nephropathy. Promotion of excessive oxidative stress in the vascular and cellular milieu results in endothelial cell dysfunction, which is one of the earliest and most pivotal metabolic consequences of chronic hyperglycemia. These derangements are caused by excessive production of advanced glycation end products and free radicals and by the subjugation of antioxidants and antioxidant mechanisms. An increased understanding of the role of oxidative stress in diabetic nephropathy has lead to the exploration of a number of therapeutic strategies, the success of which has so far been limited. However, judicious and timely use of current therapies to maintain good glycemic control, adequate blood pressure and lipid levels, along with lifestyle measures such as regular exercise, optimization of diet and smoking cessation, may help to reduce oxidative stress and endothelial cell dysfunction and retard the progression of diabetic nephropathy until more definitive therapies become available. PowerPoint Presentation: TNF, a type II transmembrane protein, is processed by TACE, which cleaves the 26 kDa membrane-bound form of TNF to the soluble 17 kDa form. TNF signaling occurs primarily via TNFR1, which is ubiquitously expressed. Binding of soluble TNF to this receptor can induce either stimulation of gene expression or induction of apoptosis. Both processes are initiated by binding of the adaptor protein TRADD, which binds directly to the TNFR1 death domain. When FADD (another adaptor protein) binds to TRADD, the signaling cascade eventually results in apoptosis. However, when TRADD binding is followed by TRAF2 and RIP binding, gene expression is stimulated through the activation of various downstream signaling pathways, including those mediated by NFκB (the major pathway activated by TNF), c-Jun N-terminal kinases or p38 MAPK. Abbreviations: FADD, Fas-associated death domain; IκB, inhibitor of NFκB; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor κB; RIP, receptor-interacting protein; TACE, TNF-converting enzyme; TNF, tumor necrosis factor; TNFR1, TNF receptor 1; TRADD, TNF-receptor type 1-associated death domain protein; TRAF2, TNF receptor-associated factor 2 PowerPoint Presentation: Figure 5 Effects of oxidative stress in early diabetic nephropathy PowerPoint Presentation: Figure 4 Glucotoxicity pathways in diabetic nephropathy PowerPoint Presentation: Organ damage can be triggered by both extracellular and intracellular hyperglycemia. Increased extracellular glucose leads to nonenzymatic glycosylation of proteins and subsequent formation of advanced glycation end products (AGE) that interact with the receptor for AGE (RAGE) on the plasma membrane and promote the production of reactive oxygen species (ROS). Increased intracellular glucose drives mitochondrial activity, increases the activity of protein kinase C (PKC) and NADPH oxidase and promotes flux through the polyol pathway, all of which effect cellular metabolism and phenotype. Excessive ROS production in the vasculature drives changes in cell phenotype that are mediated by a range of signaling pathways and transcription factors. Kidney cells also undergo cell-specific and organ-specific phenotypic changes as a result of hyperglycemia-mediated ROS production. Abbreviations: AP1, activator protein 1; AR, aldose reductase; CCL2, CC-chemokine ligand 2 (also known as MCP1); CDC42, cell division cycle 42; EGR1, early growth response protein 1; ERK, extracellular signal-regulated kinase; JAK, Janus-activated kinase; JNK, Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NF κ B, nuclear factor κ B; PI3K, phosphatidylinositol 3-kinase; RNS, reactive nitrogen species; SDH, sorbitol dehydrogenase; STAT, signal transducer and activator of transcription. Adapted wit PowerPoint Presentation: Figure 3 Reactive oxygen and reactive nitrogen species Figure 3 Reactive oxygen and reactive nitrogen species PowerPoint Presentation: Some of the prominent ROS include free radicals such as superoxide (˙O 2 − ) and hydroxyl (˙OH) and nonradical molecules such as hydrogen peroxide (H 2 O 2 ) and hypochlorous acid (HOCl). These oxidative molecules with an unpaired electron in the outer orbit are highly reactive and bring about adverse changes, when in contact with other cell structures and molecules. In addition to ROS, another group of oxidant species, the reactive nitrogen species (RNS), are major contributors to oxidative stress. The most important RNS is peroxynitrite (OONO − ), which is formed as a result of the reaction of superoxide with nitric oxide. 69 Adapted with permission from Macmillan Publishers © Lambeth, J. D. Nat. Rev. Immunol. 4, 181–189 (2004) . PowerPoint Presentation: Figure 3 Leukocyte infiltration into the diabetic kidney Navarro-González, J. F. et al. (2011) Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy Nat. Rev. Nephrol. doi:10.1038/nrneph.2011.51 PowerPoint Presentation: E-selectin, ICAM-1 and VCAM-1 are cell adhesion molecules that mediate binding of epithelial cells to each other, to other cell types (such as mesangial cells) and to the extracellular matrix. These proteins also actively control transmigration of leukocytes into renal tissue via the adhesion cascade. Circulating leukocytes move towards the endothelium and are captured (tethering). Leukocytes initially adhere transiently and roll along the endothelium. When the endothelium is activated, rolling of leukocytes is substantially slower than the movement of freely circulating leukocytes (slow rolling). Leukocyte activation is induced both directly by E-selectin-mediated slow rolling, and indirectly by signals transmitted through adjacent receptors. Leukocyte arrest is mediated by firm binding to adhesion molecules, including E-selectin, ICAM-1 and VCAM-1. Adherent leukocytes then undergo transmigration. Interactions between leukocyte integrins and their ligands also stimulate endothelial cells, further promoting leukocyte transmigration through transcellular or paracellular pathways and inducing the formation of endothelial-cell projections that express high levels of ICAM-1 and/or VCAM-1. Leukocytes infiltrating the renal tissue initiate changes that are potentially harmful for the kidney. Abbreviations: ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion protein 1. PowerPoint Presentation: Figure 4 NFκB signaling pathways in diabetic nephropathy Navarro-González, J. F. et al. (2011) Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy Nat. Rev. Nephrol. doi:10.1038/nrneph.2011.51 PowerPoint Presentation: NF κ B is a transcriptional regulator expressed in the cytoplasm of almost all cell types, where its activity is controlled by I κ Bs, a family of regulatory proteins. I κ Bs bind to the p52 subunit of NF κ B, which prevents the complex from entering the nucleus. NF κ B activation is tightly regulated by signals that degrade I κ B. In renal cells, these signals include ligand binding to TNF type 1 and type 2 receptors, T-cell receptors, B-cell receptors, and Toll-like receptor–IL-1 receptor superfamily members. Such signals activate a multisubunit I κ B kinase complex that phosphorylates I κ B. Phosphorylated I κ B undergoes proteasomal degradation, which enables free NF κ B to translocate to the nucleus, bind to promoter and enhancer sites, and activate transcription. In patients with diabetic nephropathy, NF κ B signaling results in increased transcription of target genes that encode chemokines, effector molecules of immunity, inflammatory cytokines, and cell adhesion molecules (which perpetuate inflammatory responses), as well as other molecules relevant for this complication (e.g. metalloproteinases and tissue factor). Abbreviations: I κ B, inhibitor of NF κ B; NF κ B, nuclear factor κ B; TNF, tumor necrosis factor You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.