title: Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver.
abstract: Clinical studies indicate that hepatic drug transport may be altered in chronic kidney disease (CKD). Uremic solutes associated with CKD have been found to alter the expression and/or activity of hepatocyte transporters in experimental animals and in cultured cells. However, given the complexity and adaptability of hepatic transport, it is not clear whether these changes translate into significant alterations in hepatic transport in vivo. To directly measure the effect of CKD on hepatocyte transport in vivo, we conducted quantitative intravital microscopy of transport of the fluorescent organic anion fluorescein in the livers of rats following 5/6th nephrectomy, an established model of CKD. Our quantitative analysis of fluorescein transport showed that the rate of hepatocyte uptake was reduced by ∼20% in 5/6th nephrectomized rats, consistent with previous observations of Oatp downregulation. However, the overall rate of transport into bile canaliculi was unaffected, suggesting compensatory changes in Mrp2-mediated secretion. Our study suggests that uremia resulting from 5/6th nephrectomy does not significantly impact the overall hepatic clearance of an Oatp substrate.
authors.affiliation: Division of Nephrology, School of Medicine, Indiana University, Indianapolis, Indiana; and Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Ryan
authors.affiliation: Division of Nephrology, School of Medicine, Indiana University, Indianapolis, Indiana; and Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Dunn
authors.affiliation: Division of Nephrology, School of Medicine, Indiana University, Indianapolis, Indiana; and Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana bsdecker@iu.edu.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Decker
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000378:metabolism; D001692:Biological Transport; D004195:Disease Models, Animal; D015536:Down-Regulation; D019793:Fluorescein / Q000008:administration & dosage / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D007267:Injections; D008099:Liver / Q000378:metabolism*; D008297:Male; D036641:Microscopy, Fluorescence, Multiphoton; D009392:Nephrectomy; D027361:Organic Anion Transporters / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000378:metabolism*; D013997:Time Factors
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D005456:Fluorescent Dyes; D027361:Organic Anion Transporters; D019793:Fluorescein
keywords: Mrp2; Oatp; chronic kidney disease; cytochrome P-450; hepatic transport; sodium fluorescein; uremia