Reactive Oxygen Species and NFkB Increase Peritoneal Filtration and Generate Ascites in Nephrotic Syndrome

Abstract

Clinical and experimental observations suggest that nephrotic ascites is not accounted for by hypoalbuminemia but by changes of the capillary endothelium permeability. We investigated the mechanism of these changes in puromycin aminonucleoside (PAN) nephrotic rats. The peritoneal filtration coefficient (Kf) was estimated by the slope of the regression line connecting the trans‐peritoneal gradient of osmotic pressure which was varied experimentally to the trans‐peritoneal water flux measured by osmotic dilution.Kf doubled and expression of aquaporin 1 (AQP1) increased in peritoneum of PAN rats. PAN rats displayed peritoneal oxidative stress attested by ROS accumulation and dysregulation of NADPH oxidase and ROS detoxifying enzymes expression. The ROS scavenger N‐acetyl cysteine (NAC) prevented the increase in Kf and in AQP1 expression. It also reduced by half the volume of ascites without changing renal sodium handling, albuminuria or hypoalbuminemia. PAN rats peritoneum also displayed activation of NFkB attested by increased nuclear labeling with anti‐p50 antibody. Activation of NFkB was blunted in NAC‐treated PAN rats. JSH‐23, an inhibitor of NFkB transcriptional activity, mimicked all the effects of NAC.These results show that nephrotic syndrome is associated with increased filtration coefficient of the peritoneal barrier which stems in part from increased expression of AQP1. These changes are triggered by oxidative stress and subsequent activation of NFkB. They account for at least half of increased filtration rate, the remaining stemming possibly from decreased plasma oncotic pressure.