Oxidants and iron in Chronic Kidney Disease. SUDHIR V. SHAH. Presented by Akyaw Priscilla Abena. H3Africa CKD Lab.

Outline… Introduction (Reactive Oxygen species) Biological effects of oxidants relevant to chronic kidney disease Role of oxidants in Leukocyte- dependent Glomerulonephritis Role of oxidants in Leukocyte- independent Glomerulonephritis Diabetic Nephropathy Role of oxidants and Iron in Progressive Kidney Disease Conclusion

Introduction… Reactive Oxygen Species (ROS) Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen. Examples include superoxide and peroxides. ROS are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis (metabolism of hydrogen peroxide by the neutrophil induced MPO) Normally Oxygen accepts 4 electrons and is converted directly to water. However, partial reduction of oxygen can and does occur in biological systems leading to the generation of partially reduced and potentially toxic reactive oxygen. Thus, sequential reduction of oxygen along the univalent pathway leads to the generation of radicals like the superoxide ion, hydrogen peroxide, hydroxyl radical etc. Additional oxidants may be formed as a result of the metabolism of hydrogen peroxide my neutrophil derived MPO Even though there are other external sources of radicals in the body, this paper does not concentrate on them but mainly emphasizes on the endogenous radicals Recent work has demonstrated that ROS have a role in cell signaling, including; apoptosis; gene expression; and the activation of cell signaling cascades .

Biological effects of oxidants relevant to chronic kidney disease Occurrence of Proteinuria Altered glomerular filtration rate Morphologic changes These effects are relevant both to various proliferative and nonproliferative glomerulonephritis and diabetic nephropathy

Occurrence of Proteinuria Damage to GBM is the major cause of Proteinuria. Caused by Leukocytes causing damage to GBM due to stimulation of gelatinase by HOCl Increase in susceptibility to proteolytic damage by inactivating the alpha-1- proteinase inhibitor, thus allowing the release of neutrophil elastase (causing damage to the extracellular matrix). Impairment of the synthesis of glomerular heparin sulfate proteoglycans, needed to maintain the integrity of GBM and also normalize GUF. There are several in vivo studies to prove that oxidants are capable of inducing Proteinuria that leads to glomerular injury

Role of oxidants in Leukocyte- dependent Glomerulonephritis Several studies strongly support the role of leukocytes in causing glomerular injury that results in proteinuria

Anti-GBM antibody disease(autoimmune diseases). When the body's immune system functions properly, it creates protein-like substances called antibodies and immunoglobulins to protect the body against invading organisms. In an autoimmune disease, the immune system creates autoantibodies, which are antibodies or immunoglobulins that attack the body itself. Autoimmune diseases may be systemic and affect many parts of the body, or they may affect only specific organs or regions This is done by the production of large amounts of superoxide ions in the particularly organ or region, in this case the glomerulus. Although the role of iron is not completely understood, the protective effect of iron chelators generally has been taken as evidence for the participation of hydroxyl radical tissue injury, because iron is critical in the generation of the hydroxyl radical. Fe2+ + H2O2 → Fe3+ + OH· + OH− superoxide hydroxyl radicals

Anti-GBM Antibody disease (GPS) Good pasture syndrome is an autoimmune disorder. It occurs when the immune system mistakenly attacks and destroys healthy body tissue. Persons with this syndrome develop substances that attack a protein called collagen in the tiny air sacs in the lungs and the filtering units (glomeruli) of the kidneys. Causes of GPS remains unknown, but it is believed that an insult to the blood vessels taking blood from and to the lungs is required in order to allow the anti-GBM antibodies to come into contact with the alveoli. Insults include; exposure to organic solvents (eg. chloroform) and hydrocarbons, exposure to tobacco smoke, high oxygen environments, cocaine inhalation etc.

Glomerular filtration rate. Oxidants reduce glomerular and mesangial cell planar surface and increase myosin light chain phosphorylation, a biological chemical marker of contraction. These effects could modulate the surface area of mesangial cells, thus modifying ultrafiltration coefficient and leading to a decrease in the GFR The synthesis of thromboxane and prostaglandins are also believed to be increased by oxidants and have been implicated as important mediators causing proteinuria and/or a fall in GFR in various experimental models.

Role of oxidants in Leukocyte- independent Glomerulonephritis

Passive Heymann nephritis model of membranous nephropathy

Diabetic Nephropathy There is a large body of evidence indicating that diabetes is a state of increased oxidative stress. Hyperglycemia results in overproduction of oxygen free radicals, which contributes to the progression of diabetes (by mesangial cells). High glucose produces reactive oxygen species as a result of glucose auto-oxidation metabolism, and the development of advanced glycosylation end products. In a review,Nishikawa and Brownlee argue that oxidants are the causative link for all the major pathways that have been implicated in diabetic complications including activation of aldose reductase pathway, induction of the diacylglycerol pathway and activation of Protein Kinase C. High glucose has also been shown to affect several biologic processes in glomeruli that have been implicated in diabetic nephropathy, and antioxidants have been shown to inhibit these processes..(eg. antioxidants prevented the glucose induced activation of PKC and NK-ƙ𝐵..etc.)

glucose induced activation of Protein kinase C - Google Search

Role of oxidants and Iron in Progressive Kidney Disease The precise cellular mechanisms by which oxidants and iron participate in progression are not known. However, oxidants and iron have many cellular effects that are potentially important in tubulointerstitial damage, fibrosis and matrix accumulation, eg. It is well established that oxidants and iron play an important role in cellular injury and cell death, including apoptosis. Thus conceivably they could play a role in tubular atrophy and loss of cells, which is a common feature of progressive renal disease.

Conclusion A sufficient body of in vitro and in vivo information exists to postulate that oxidants appear to be important mediators in glomerular pathophysiology and in progressive kidney diseases. While the collective information on the role of oxidants and iron derived from both models of glomerular disease, as well as progressive renal failure is impressive ,there is virtually no information on the potential role of these mechanisms in human disease There are many differences between animal models of glomerular disease and glomerular disease of humans.

Draw Backs…??? Almost all experimental models used or cited are from literature and/or work done by other researchers. Mechanisms of all reactions are not visualized or illustrated Paper does not conclusively decide on weather Oxidants and iron actually leads to the progression of CKD