Superoxide Dismutase Mimetic Preserves the Glomerular Capillary Permeability Barrier to Protein

Abstract

Overproduction of superoxide (O 2 . ) occurs in glomerular disease and may overwhelm the capacity of superoxide dismutase (SOD), thereby intensifying oxidant injury by O 2 . and related radical species that disrupt the glomerular capillary permeability barrier to protein. We examined the efficacy of the SOD mimetic tempol in preserving glomerular permeability to protein using 1) a rat model of glomerular immune injury induced by an antiglomerular basement membrane antibody (anti-GBM), and 2) isolated rat glomeruli in which injury was induced by the cytokine tumor necrosis factor-␣ (TNF␣). To induce glomerular immune injury, rats received anti-GBM using a protocol that results in prominent infiltration of glomeruli by macrophages and in which macrophage-derived TNF␣ has been shown to mediate albuminuria. To increase glomerular capillary permeability to albumin (P alb ) ex vivo, isolated glomeruli were incubated with TNF␣ at concentrations (0.5-4.0 g/ml) known to stimulate O 2 . production. Increments in P alb were detected by measuring changes in glomerular volume in response to an applied oncotic gradient. Significant increases in the urine excretion of albumin and F 2␣ -isoprostane were observed in rats with glomerular immune injury without a significant change in systolic blood pressure. Tempol treatment significantly reduced urine isoprostane and albumin excretion. In isolated glomeruli, TNF␣ increased P alb and tempol abrogated this effect, both in a dose-dependent manner. These observations indicate that SOD mimetics can preserve the glomerular permeability barrier to protein under conditions of oxidative stress from O 2 . production.

N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy

“…4). It has been demonstrated that oxidative stress plays a significant role in an increased glomerular filtration barrier permeability (15,33,34) and development of different kidney diseases, including adriamycin-induced injury (4), podocyte damage, and diabetic nephropathy progression (13,42). Our findings indicate that glomerular hemorrhage in WRN is independent of oxidative stress.…”

LIM homeobox transcription factor 1B expression affects renal interstitial fibrosis and apoptosis in unilateral ureteral obstructed rats

“…Furthermore, Kida et al and Sato et al determined that a positive linear relationship exists between tubular dilatation and tubular epithelial apoptosis in UUO mice (18). Increased ROS, lipid peroxidation, and compromised antioxidants were previously found in a number of studies using obstructed rodent kidneys (6,24,35,48), and ROS have been suggested to impair the integrity of the glomerular basement membrane, reduce podocyte proteoglycan de novo synthesis, and stimulate factors promoting ECM deposition, including TGF-␤ 1 (9), as similarly observed in the present study. Overall, these results corroborate our results in the RTEC model system.…”

Elevated Glucose Impairs the Endothelial Cell Response to Shear Stress

“…As such, free radical scavengers such as Tempol have been used extensively to ameliorate many of the biochemical abnormalities induced by hyperglycemia, including reduction of oxidant stress, in both in vitro cell culture and in vivo animal studies. 19,41 The contribution of ROS in our experimental system was studied by incubating HAECs with high glucose in the presence of 1 mM Tempol. Our results show that the glucose-induced impairment of flowinduced elongation and alignment occurs even in the presence of Tempol.…”

“…We first investigated the effect of ROS on the endothelial alignment response to flow using the common superoxide dismutase mimetic and free radical scavenger Tempol. 19,41 In representative images of shear-exposed cells (shown in Figs. 4a-4d), cells grown in 30.5 mM glucose + 1 mM Tempol 41 (Fig.…”