title: Uremic Toxins Induce ET-1 Release by Human Proximal Tubule Cells, which Regulates Organic Cation Uptake Time-Dependently.
abstract: In renal failure, the systemic accumulation of uremic waste products is strongly associated with the development of a chronic inflammatory state. Here, the effect of cationic uremic toxins on the release of inflammatory cytokines and endothelin-1 (ET-1) was investigated in conditionally immortalized proximal tubule epithelial cells (ciPTEC). Additionally, we examined the effects of ET-1 on the cellular uptake mediated by organic cation transporters (OCTs). Exposure of ciPTEC to cationic uremic toxins initiated production of the inflammatory cytokines IL-6 (117 ± 3%, p < 0.001), IL-8 (122 ± 3%, p < 0.001), and ET-1 (134 ± 5%, p < 0.001). This was accompanied by a down-regulation of OCT mediated 4-(4-(dimethylamino)styryl)-N-methylpyridinium-iodide (ASP+) uptake in ciPTEC at 30 min (23 ± 4%, p < 0.001), which restored within 60 min of incubation. Exposure to ET-1 for 24 h increased the ASP+ uptake significantly (20 ± 5%, p < 0.001). These effects could be blocked by BQ-788, indicating activation of an ET-B-receptor-mediated signaling pathway. Downstream the receptor, iNOS inhibition by (N(G)-monomethyl-l-arginine) l-NMMA acetate or aminoguanidine, as well as protein kinase C activation, ameliorated the short-term effects. These results indicate that uremia results in the release of cytokines and ET-1 from human proximal tubule cells, in vitro. Furthermore, ET-1 exposure was found to regulate proximal tubular OCT transport activity in a differential, time-dependent, fashion.
authors.affiliation: Department of Pediatric Nephrology, Radboudumc 6525 GA Nijmegen, The Netherlands. carolien.schophuizen@gmail.com.
authors.forename: Carolien M S
authors.initials: CM
authors.lastname: Schophuizen
authors.affiliation: Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboudumc 6525 GA Nijmegen, The Netherlands. joost.hoenderop@radboudumc.nl.
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboudumc 6525 GA Nijmegen, The Netherlands. r.masereeuw@uu.nl.|Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99 (room 2.72), 3584 CG Utrecht, The Netherlands. r.masereeuw@uu.nl.
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.affiliation: Department of Pediatric Nephrology, Radboudumc 6525 GA Nijmegen, The Netherlands. bert.vandenheuvel@radboudumc.nl.|Department of Pediatrics, Catholic University Leuven, 3000 Leuven, Belgium. bert.vandenheuvel@radboudumc.nl.
authors.forename: Lambert P van den
authors.initials: LP
authors.lastname: Heuvel
keywords: cytokines; endothelin signaling; iNOS; organic cation transport; protein kinase C; uremic toxins