Effects of chronic kidney disease on liver transport: Quantitative intravital microscopy of fluorescein transport in the rat liver

Jennifer C. Ryan, Kenneth Dunn, Brian Decker

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)R1488-R1492
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume307
Issue number12
DOIs
StatePublished - Dec 15 2014

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Fluorescein
Chronic Renal Insufficiency
Liver
Hepatocytes
Nephrectomy
Bile Canaliculi
Uremia
Anions
Cultured Cells
Down-Regulation
Intravital Microscopy
Pharmaceutical Preparations

Keywords

  • Chronic kidney disease
  • Cytochrome P-450
  • Hepatic transport
  • Mrp2
  • Oatp
  • Sodium fluorescein
  • Uremia

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

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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.",
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