Oxidative Stress in IgA Nephropathy

IgA nephropathy (IgAN) is characterized by mesangial deposits of IgA1, likely due to accumulation of IgA immune complexes. The activation of intracellular signaling mostly results in oxidative stress, as detected in mesangial cells cultured with aberrantly glycosylated IgA or IgA aggregates and in renal biopsies of patients with IgAN. Signs of altered oxidation/antioxidation balance have been detected in sera and/or in erythrocytes of patients with IgAN, including increased levels of lipoperoxide or malondialdehyde and reduced activity of superoxide dismutase, catalase and glutathione peroxidase. Moreover, increased levels of a marker of oxidative stress, advanced oxidation protein products (AOPPs), have been reported to be significantly associated with proteinuria and disease progression in patients with IgAN. AOPPs are often carried by albumin and can in turn enhance the oxidative stress in the circulation. Recent research suggests that the nephrotoxicity of aberrantly glycosylated IgA1 in IgAN is enhanced in the presence of systemic signs of oxidative stress, and it is tempting to hypothesize that the level of the oxidative milieu conditions the different expression and progression of IgAN. Copyright © 2010 S. Karger AG, Basel Published online: July 2, 2010 Rosanna Coppo, MD Regina Margherita University Hospital Piazza Polonia 94 IT–10126 Turin (Italy) Tel. +39 011 313 5848, E -Mail rosanna.coppo @ unito.it © 2010 S. Karger AG, Basel 1660–2110/10/1163–0196$26.00/0 Accessible online at: www.karger.com/nec D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 4: 52 :5 7 A M Oxidative Stress in IgA Nephropathy Nephron Clin Pract 2010;116:c196–c199 c197 crease in important intracellular and circulating antioxidants, of which thiol groups of albumin are quantitatively the most important [3] . Besides uremia, experimental evidence supports the role of oxidants not only in inducing tubulointerstitial damage which accompanies progression, but also in the early stages of glomerular damage [4] . Enhanced generation of oxidants by infiltrating leukocytes has been demonstrated in anti-Thy1.1 and antiGBM-induced glomerulonephritis, and plays a major role in inducing exudative and proliferative glomerular changes. Leukocytes are thought to cause proteinuria by degrading the glomerular basement membrane activating a latent metalloproteinase by HOCl or a similar oxidant generated by the myeloperoxidase-H 2 O 2 -halide system. Proteinuric experimental models lacking infiltrating leukocytes, like nephrosis induced by injection of puromycin aminonucleoside, have also demonstrated a role of oxidants. The role of oxidative stress in inducing proteinuria is supported by a recent report which detects a causative link between advanced oxidation protein products (AOPPs) and podocyte depletion [5] . AOPPs are a family of oxidized, dityrosine-containing protein-insoluble products, resistant to proteolysis, generated by oxidative stress associated with monocyte activation, myeloperoxidase release, and production of reactive oxygen species. Increased levels of AOPPs are associated with high proteinuria, monocyte interstitial infiltration and glomerulosclerosis in murine models of remnant kidneys. AOPPs activate the intrarenal redox-sensitive pathway with nuclear translocation of nuclear factor  B (NF B) and synthesis of pro-inflammatory and pro-sclerotic mediators [6] . AOPPs induce podocyte apoptosis when injected in experimental animals and when incubated in podocyte cultures at remarkably low doses. AOPPs induce intracellular superoxide generation in podocytes by a mechanism involving nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The cascade of intracellular signaling events finally leads to p53-dependent apoptosis [5] . The conclusion from this recent report suggests that AOPP-mediated apoptosis plays a critical role in promoting proteinuria and accelerating glomerular sclerosis. Activation of the Oxidative Stress Pathway in IgAN The activation of intracellular signaling mostly results in oxidative stress, as detected in mesangial cells cultured with aberrantly glycosylated IgA or IgA aggregates [7, 8] and in renal biopsies of patients with IgAN, similar to what has been detected in diabetic nephropathy [9] . Signs of altered oxidation/antioxidation balance have been detected in sera and/or in erythrocytes of patients with IgAN, including increased levels of lipoperoxide or malondialdehyde and reduced activity of superoxide dismutase, catalase and glutathione peroxidase [10, 11] . Moreover, increased levels of AOPPs have been recently reported to be significantly associated with proteinuria and disease progression in patients with IgAN [12] . AOPPs are often carried by albumin and can in turn enhance the oxidative stress in the circulation. AOPPs are detected in patients with advanced chronic renal failure, but in IgAN they are independent early predictors of poor renal outcome [12] . Variable Natural History of IgAN One of the most fascinating and still unanswered questions concerning IgAN is the extreme variability of natural history in individual patients, ranging from rapidly progressive cases to ‘lanthanic’ IgA innocent deposits (4–16%; averaging about 70,000 per million population) [13] . It can be debated whether these are ‘innocent’ findings or whether these subjects represent a state of ‘pre-disease’ awaiting another event (a second ‘hit’) to bring the disease to full clinical and recognizable expression. Moreover, the disease can show no sign of progression at all even after decades in 5–50% of patients, or progress to end-stage renal failure within 20 years in 80% of patients. New Working Hypothesis on Pathogenesis of