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

Cells

Carolien M. S. Schophuizen³  Joost G. J. Hoenderop¹  Rosalinde Masereeuw²  Lambert P. van den Heuvel³ 

[1] Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboudumc 6525 GA Nijmegen, The Netherlands; E-Mail:;Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboudumc 6525 GA Nijmegen, The Netherlands;Department of Pediatric Nephrology, Radboudumc 6525 GA Nijmegen, The Netherlands; E-Mails:

关键词: uremic toxins;    endothelin signaling;    cytokines;    organic cation transport;    iNOS;    protein kinase C;   

DOI  :  10.3390/cells4030234

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.