Oxidative Stress and Nuclear Factor κB (NF-κB) Increase Peritoneal Filtration and Contribute to Ascites Formation in Nephrotic Syndrome

Abstract

Water accumulation in the interstitium (edema) and the peritoneum (ascites) of nephrotic patients is classically thought to stem from the prevailing low plasma albumin concentration and the decreased transcapillary oncotic pressure gradient. However, several clinical and experimental observations suggest that it might also stem from changes in capillary permeability. We addressed this hypothesis by studying the peritoneum permeability of rats with puromycin aminonucleosideinduced nephrotic syndrome. The peritoneum of puromycin aminonucleoside rats displayed an increase in the water filtration coefficient of paracellular and transcellular pathways, and a decrease in the reflection coefficient to proteins. It also displayed oxidative stress and subsequent activation of NF-B. Scavenging of reactive oxygen species and inhibition of NF-B prevented the changes in the water permeability and reflection coefficient to proteins and reduced the volume of ascites by over 50%. Changes in water permeability were associated with the overexpression of the water channel aquaporin 1, which was prevented by reactive oxygen species scavenging and inhibition of NF-B. In conclusion, nephrotic syndrome is associated with an increased filtration coefficient of the peritoneum and a decreased reflection coefficient to proteins. These changes, which account for over half of ascite volume, are triggered by oxidative stress and subsequent activation of NF-B. Nephrotic syndrome (NS)3 is a multifactorial glomerular disease defined by massive proteinuria and hypoalbuminemia. Irrespective of its etiology, NS is commonly associated with renal retention of sodium leading to the generation of ascites and/or edema (1, 2). Association of sodium retention with edema rather than with hypertension suggests that fluid flux across the capillary endothelium increases, and accordingly the capillary filtration capacity is 2-fold higher in nephrotic patients (3). Classically, this increase is thought to stem from hypoalbuminemia and a decreased oncotic gradient across the capillary wall. However, several observations militate against this theory: 1) the transcapillary gradient of oncotic pressure is almost unchanged in nephrotic patients (4, 5); 2) during steroid-induced remission of nephrotic syndrome, natriuresis resumes and edema decreases before normalization of serum albumin levels (6); and 3) diuretic treatments reduce edema without significantly changing the oncotic pressure gradient (5). Consequently, a new concept has emerged according to which the asymmetry of volume expansion in NS results from alterations of the intrinsic properties of the endothelial filtration barrier, i.e. its water permeability and/or its reflection coefficient to proteins. However, this hypothesis has not been demonstrated experimentally, and neither the molecular basis of these capillary alterations nor their connection to proteinuria and/or hypoalbuminemia is elucidated. Several studies have highlighted the pathophysiological importance of reactive oxygen species (ROS) in ...

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