The role of transport proteins for the elimination of uremic toxins during chronic kidney disease

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Chronic kidney disease (CKD) is associated with an increase of uremic toxins in plasma accompanied by a variety of clinical symptoms such as arterial hypertension. Because the plasma concentrations of uremic toxins further elevate during dialysis treatment, an enhancement of the transporter-mediated tubular secretion of toxins could be beneficial for patients with CKD. So far, little is known about transporters in proximal tubular cells mediating the secretion of uremic toxins from blood into urine. Therefore, studies on the role of transport proteins for the renal elimination of uremic toxins is in the focus of this research project. Toyohara and coworkers demonstrated that the recombinant overexpression of the human uptake transporter OATP4C1 in rat kidney reduced hypertension, cardiomegaly and inflammation in the setting of renal failure. In addition, OATP4C1 overexpression decreased plasma levels of uremic toxins such as ADMA and guanidine succinate suggesting that this transporter plays a role in the transport of uremic toxins. Furthermore, several apically localized export pumps such as P-glycoprotein (P-gp) and BCRP have been identified as possible transporters of uremic toxins. To gain more insights into the role of transport proteins in the renal secretion of uremic toxins four sub-projects will be addressed. Using established stably-transfected HEK293 cells recombinantly overexpressing OATP4C1, uremic toxins will be investigated as modulators and substrates of OATP4C1-mediated transport. Furthermore, using double-transfected MDCKII cells recombinantly overexpressing OATP4C1 together with an apically localized export pump such as MRP2, MRP4, BCRP or P-gp, the vectorial transport of uremic toxins should be studied. For both sub-projects several uremic toxins and toxin metabolites will be provided by Prof. Dr. Masereeuw (University Medical Center, Nijmegen, The Netherlands). The regulation of the investigated transporters by uremic toxins will be addressed by analyzing their expression in murine and human primary proximal tubule cells treated with different concentrations of uremic toxins. Prof. Dr. Klaus Höcherl (Department of Pharmacology, Friedrich-Alexander-Universität Erlangen-Nürnberg) will provide murine primary proximal tubule cells (PTCs) for this analysis. Finally, the expression of OATP4C1 and of the export pumps MRP2, MRP4, BCRP and P-gp will be analyzed in different human chronic kidney diseases. In a collaboration with the nephropathology department, the expression of the transporters will be quantified in proximal tubule cell samples originating from tissue biopsies of different chronic kidney diseases and isolated by microdissection. The goal of this research project is to get an insight into the role of transport proteins in the tubular secretion of uremic toxins and into the regulation of these transporters under pathophysiological conditions to gain access to a possible pharmacological treatment of patients with CKD.