Oxidative stress in the pathogenesis of experimental mesangial proliferative glomerulonephritis

Abstract

Reactive oxygen species (ROS) are increasingly believed to be important intracellular signaling molecules in mitogenic pathways involved in the pathogenesis of glomerulonephritis (GN). We explored the effects of the antioxidants alpha-lipoic acid and N-acetyl-l-cysteine on ERK activation in cultured mesangial cells and the role of ERK activation in the severity of glomerular injury in a rat model of anti-Thy 1 GN. In cultured mesangial cells, growth factors stimulated ERK phosphorylation by 150-450%. Antioxidants reduced this increase by 50-60%. Induction of anti-Thy 1 nephritis in rats led to a 210% increase in glomerular ERK phosphorylation. This increase in phosphorylated ERK was reduced by 50% in animals treated with alpha-lipoic acid. Treatment with alpha-lipoic acid resulted in significant improvement of glomerular injury. Cellular proliferation was reduced by 100%, and the number of proliferating cell nuclear antigen-positive cells was reduced by 64%. The increased expression of glomerular transforming growth factor-beta1 protein and mRNA in rats with anti-Thy 1 nephritis was significantly attenuated and mesangial cell transformation into myofibroblasts was completely prevented by treatment with alpha-lipoic acid. The effects of alpha-lipoic acid were at least partially due to inhibition of oxidative stress. In rats with anti-Thy 1 nephritis, ROS production was increased 400-500%, and this increase was inhibited by 55% by treatment with alpha-lipoic acid. We suggest that ROS may mediate glomerular injury by inducing ERK phosphorylation. alpha-Lipoic acid should be considered a potential therapeutic agent in certain types of human GN.

Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation

“…Conversely, ROS-independent effects do not appear to contribute significantly to AGE-induced renal tissue injury. This observation is in agreement with previous studies, indicating that interventions aimed at reducing oxidative stress are effective in preventing different types of experimental renal disease [43][44][45][46] and that amelioration of diabetic and nondiabetic renal and cardiovascular disease observed in the p66 Shc KO mouse model is associated with reduction of oxidative stress [34][35][36][37][38].…”

Oxidative Stress in 5/6 Nephrectomized Rat Model: Effect of Alpha-Lipoic Acid

“…The RK model is widely considered to be a classic model of CKD. Abundant evidence has accumulated indicating that CKD causes oxidative stress [15][16][17] and oxidative stress accelerates the progression of renal injury directly by inducing cytotoxicity and indirectly by promoting inflammation. 1,[16][17][18] Oxidative stress is a known feature of CKD, and its presence is evidenced by the reported elevation of lipid peroxidation products, MDA, and depressed antioxidant capacity.…”

Addition of the Antioxidant Probucol to Angiotensin II Type I Receptor Antagonist Arrests Progressive Mesangioproliferative Glomerulonephritis in the Rat

“…Our findings that an ARB, candesartan, considerably reduced proteinuria, the level of TGF-␤1, and ECM accumulation at the late stage in this rat model of GN and finally inhibited the progression of glomerulosclerosis are consistent with the above concept. ROS has been implicated in the development and progression of GN (15)(16)(17)40,41). NADPH oxidase is a major source of ROS in phagocytes as well as non-phagocytic cells, including fibroblasts, vascular smooth muscle cells, and glomerular cells (21)(22)(23)(24)(25).…”

“…Recently, reactive oxygen species (ROS) that are produced by NADPH oxidase has been implicated in the development and progression of GN (15)(16)(17). The administration of various natural or synthetic antioxidants has been shown to be beneficial in the prevention and attenuation of renal scarring in numerous animal models of renal disease (18).…”