Chronic Uremia Induces Permeability Changes, Increased Nitric Oxide Synthase Expression, and Structural Modifications in the Peritoneum

Abstract

Abstract. Advanced glycation end products (AGE), growth factors, and nitric oxide contribute to alterations of the peritoneum during peritoneal dialysis (PD). These mediators are also involved in chronic uremia, a condition associated with increased permeability of serosal membranes. It is unknown whether chronic uremiaper semodifies the peritoneum before PD initiation. A rat model of subtotal nephrectomy was used to measure peritoneal permeability after 3, 6, and 9 wk, in parallel with peritoneal nitric oxide synthase (NOS) isoform expression and activity and structural changes. Uremic rats were characterized by a higher peritoneal permeability for small solutes and an increased NOS activity due to the up-regulation of endothelial and neuronal NOS. The permeability changes and increased NOS activities correlated with the degree of renal failure. Focal areas of vascular proliferation and fibrosis were detected in uremic rats, in relation with a transient up-regulation of vascular endothelial growth factor and basic fibroblast growth factor, as well as vascular deposits of the AGE carboxymethyllysine and pentosidine. Correction of anemia with erythropoietin did not prevent the permeability or structural changes in uremic rats. Thus, in this rat model, uremia induces permeability and structural changes in the peritoneum, in parallel with AGE deposits and up-regulation of specific NOS isoforms and growth factors. These data suggest an independent contribution of uremia in the peritoneal changes during PD and offer a paradigm to better understand the modifications of serosal membranes in uremia.

Vascular endothelial growth factor-mediated peritoneal neoangiogenesis in peritoneal dialysis

“…50,51 Combet et al confirm an independent contribution of uremia in the peritoneal changes during PD, especially for peritoneal neoangiogenesis, with increased levels of peritoneal nitric oxide synthase (NOS) isoform, AGEs and VEGF from a rat model of subtotal nephrectomy. 52 Enhanced NOS activity and endothelial NOS up-regulation are considered as a reasonable explanation for peritoneal morphologic changes (angiogenesis and increased endothelial area), which are based on the biologic relevance between NOS and vascular density. 13 New research points out that microRNA (miRNA)-92a is induced by uremic toxin-mediated oxidative stress in endothelial cells and involved in angiogenesis and atherosclerosis.…”

Dual therapy with an angiotensin receptor blocker and a JAK1/2 inhibitor attenuates dialysate-induced angiogenesis and preserves peritoneal membrane structure and function in an experimental CKD rat model

“…Uraemia induces structural PM pathology even prior to PD initiation. 13,14 However, during PD, further compromise is driven by continued oxidant injury, inflammation and a crescendo of chemokine, cytokine and growth factor elaboration by resident PM cells and infiltrating fibroblasts and mononuclear cells. 15,16 The mesothelium undergoes recurrent denudation and regeneration.…”

The Gut-Peritoneum Axis in Peritoneal Dialysis and Peritoneal Fibrosis

“… 16 , 17 In a CKD model, fibrotic changes and advanced glycosylation end accumulation were seen in the peritoneum of rats within 3-6 weeks of uremia, before exposure to glucose-containing solutions. 18 …”