Abstract
Chronic kidney disease (CKD) is accompanied by accumulating levels of uremic solutes in the circulation. Changes in the size and composition of the bile acid pool have also been observed. We investigated via which mechanisms uremic solutes may interfere with hepatocyte function and thus contribute to altered bile acid handling. We studied interference on the level of bile acid synthesis by cytochrome P450 7A1 (CYP7A1), explored effects on hepatic bile acid transporters, and investigated effects on mitochondrial function. In HEK293 cells overexpressing bile salt transporters, we observed that p-cresyl sulfate inhibited Na+-taurocholate cotransporting polypeptide (NTCP)-mediated uptake of taurocholic acid (TCA), whereas organic anion-transporting polypeptide 1B1 (OATP1B1)-mediated TCA uptake was increased. Assays in transporter-overexpressing membrane vesicles revealed that kynurenic acid inhibited TCA transport via the bile salt efflux pump (BSEP), whereas p-cresyl glucuronide and hippuric acid increased TCA efflux via multidrug resistance-associated protein 3 (MRP3). Moreover, indoxyl sulfate decreased mRNA expression of NTCP, OATP1B3 and CYP7A1 in primary human hepatocytes. Transport studies confirmed a decreased TCA uptake in indoxyl sulfate-exposed hepatocytes. Decreased hepatocyte viability was found for all seven uremic solutes tested, whereas five out of seven also decreased intracellular ATP levels and mitochondrial membrane potential. In conclusion, uremic solutes affect hepatic bile acid transport and mitochondrial function. This can contribute to the altered bile acid homeostasis observed in CKD patients.
Highlights
Chronic kidney disease (CKD) is characterized by increasing loss of kidney-mediated clearance of waste products present in blood and constitutes a severe burden on patient health
The effect of uremic solutes on the uptake of taurocholic acid (TCA) was determined by incubating HEK293 cells overexpressing one of the human bile acid uptake transporters selected from the screen described above or enhanced Yellow Fluorescent Protein (EYFP) with radiolabeled TCA, in the presence or absence of 500 μM of one of the uremic solutes
We investigated the effect of uremic solutes on hepatic bile acid uptake, efflux and synthesis, as well as mitochondrial function that could play a role in chronic kidney disease-induced liver injury
Summary
Chronic kidney disease (CKD) is characterized by increasing loss of kidney-mediated clearance of waste products present in blood and constitutes a severe burden on patient health. As the effects of uremic solutes on hepatic drug metabolism and excretion are known to be partly mediated via hepatic drug transporters (Sun et al, 2004; Tsujimoto et al, 2008), we hypothesized that uremic solutes could contribute to the observed changes in the bile acid pool of CKD patients. An alternative basolateral pathway for the export of conjugated bile acids during cholestasis is provided by MRP3, and by MRP4 supposedly in cotransport with glutathione (Halilbasic et al, 2013) Together, these transporters modulate bile acid uptake from portal blood into hepatocytes, while preventing cytotoxic bile acid levels via their efflux from the hepatocyte. In order to comprehensively chart relevant effects of uremic solutes on hepatic bile acid handling, we included studies to identify possible mitochondrial effects of uremic solutes to investigate whether both mechanisms coincide in CKD-induced liver injury
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