Next Article in Journal
The Possible Roles of the Dentate Granule Cell’s Leptin and Other Ciliary Receptors in Alzheimer’s Neuropathology
Next Article in Special Issue
Nephron Patterning: Lessons from Xenopus, Zebrafish, and Mouse Studies
Previous Article in Journal / Special Issue
Recent Advances in Elucidating the Genetic Mechanisms of Nephrogenesis Using Zebrafish
Article Menu

Export Article

Open AccessArticle
Cells 2015, 4(3), 234-252; doi:10.3390/cells4030234

Uremic Toxins Induce ET-1 Release by Human Proximal Tubule Cells, which Regulates Organic Cation Uptake Time-Dependently

1
Department of Pediatric Nephrology, Radboudumc 6525 GA Nijmegen, The Netherlands
2
Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboudumc 6525 GA Nijmegen, The Netherlands
3
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboudumc 6525 GA Nijmegen, The Netherlands
4
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99 (room 2.72), 3584 CG Utrecht, The Netherlands
5
Department of Pediatrics, Catholic University Leuven, 3000 Leuven, Belgium
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Christoph Englert
Received: 2 May 2015 / Revised: 12 June 2015 / Accepted: 19 June 2015 / Published: 26 June 2015
(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)
View Full-Text   |   Download PDF [1543 KB, uploaded 26 June 2015]   |  

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. View Full-Text
Keywords: uremic toxins; endothelin signaling; cytokines; organic cation transport; iNOS; protein kinase C uremic toxins; endothelin signaling; cytokines; organic cation transport; iNOS; protein kinase C
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Schophuizen, C.M.S.; Hoenderop, J.G.J.; Masereeuw, R.; Heuvel, L.P. Uremic Toxins Induce ET-1 Release by Human Proximal Tubule Cells, which Regulates Organic Cation Uptake Time-Dependently. Cells 2015, 4, 234-252.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Cells EISSN 2073-4409 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top