Pyridoxamine improves functional, structural, and biochemical alterations of peritoneal membranes in uremic peritoneal dialysis rats

Abstract

We previously suggested that biochemical alterations of peritoneal membrane associated with long-term peritoneal dialysis might be, at least in part, accounted for by reactive carbonyl compounds overload originating both from uremic circulation and heat sterilization of glucose peritoneal dialysis fluid. In the present study, we utilized a uremic rat model on peritoneal dialysis and evaluated the protective effects of pyridoxamine, a recently developed inhibitor of advanced glycation end product (AGE), on structural, functional, and biochemical alterations of peritoneal membrane. Uremic rats were generated by subtotal nephrectomy, some of which were undergone peritoneal dialysis with dialysate and/or given intraperitoneal pyridoxamine. Functional [dialysate/plasma ratio (D/P)(urea, creatinine), D/D(0 glucose)], structural (density of blood vessels in peritoneal membrane tissues), and molecular biochemical [formation of pentosidine, an AGE, by high-performance liquid chromatography (HPLC) assay and expressions of vascular endothelial growth factor (VEGF), and fibroblast growth factor 2 (FGF-2), by semiquantitative polymerase chain reaction (PCR) and/or immunohistochemistry] alterations of peritoneal membrane were assessed. Uremic peritoneal membrane was characterized by an increased functional area of exchange for small solutes between blood and dialysate, vascular proliferation, increased AGE genesis, and up-regulated expressions of angiogenic cytokines. The peritoneal membrane alterations associated with peritoneal dialysis are similar but more severe than those in uremia without peritoneal dialysis. Pyridoxamine given in uremic rats with peritoneal dialysis significantly improved functional and structural alterations. This improvement was accompanied by reduction of AGE accumulation and of angiogenic cytokines expressions. Peritoneal carbonyl stress derived from uremia as well as peritoneal dialysis procedure might contribute to the vascular proliferation through induction of bioactive molecules and to an increased functional area, eventually leading to ultrafiltration failure. Pyridoxamine may be beneficial in protection of uremic peritoneal membrane on peritoneal dialysis.