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Altered Expression and Function of Hepatic Transporters in a Rodent Model of Polycystic Kidney Disease

Jacqueline Bezençon1, James J Beaudoin1, Katsuaki Ito1

  • 1Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.B., J.J.B., K.I., D.F., K.L.R.B.); DMPK Research Department, Teijin Pharma Limited, Hino, Tokyo, Japan (K.I.); Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland (S.E.R.); and Brock Scientific Consulting, Montgomery Village, Maryland (W.J.B.).

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|June 5, 2019
PubMed

Insights

Polycystic kidney disease (PKD) alters liver transporters, decreasing their expression and function. This impacts how the liver processes substances, potentially contributing to disease progression in autosomal dominant polycystic kidney disease (ADPKD).

Area of Science:

  • Hepatology
  • Nephrology
  • Pharmacology

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited kidney disorder leading to kidney failure.
  • Increased bile acids and altered liver transporters are observed in rodent models of PKD, but hepatic transporter impact remains unclear.
  • Polycystic kidney (PCK) rats, a model for PKD, exhibit liver and kidney cyst development.

Purpose of the Study:

  • To investigate hepatic transporter expression and function in PCK rats compared to wild-type (WT) Sprague-Dawley rats.
  • To determine the impact of PKD on the liver's ability to transport substances.

Main Methods:

  • Quantitative polymerase chain reaction (qPCR) for transporter gene expression.
  • Western blot and liquid chromatography-tandem mass spectroscopy (LC-MS/MS) for protein quantification.
  • Isolated perfused livers (IPLs) to assess transporter function and measure biliary excretion.
  • Measurement of biliary and hepatic total glutathione content.

Main Results:

  • Decreased protein expression of Mrp2 and Oatp1a4 in PCK rat livers (3.0-fold and 2.9-fold, respectively).
  • Proteomic analysis confirmed reduced Mrp2 and Oatp1a1 expression in PCK rats.
  • Significantly reduced biliary excretion of a multi-substrate (Oatp1a1, Mrp2, Mrp3) fluorescent dye in PCK rat IPLs (28-fold decrease).
  • Total glutathione levels were significantly lower in the bile of PCK rats.

Conclusions:

  • PKD is associated with significant alterations in hepatic transporter expression, including Mrp2 and Oatp family members.
  • Impaired transporter function in PCK rats affects the biliary excretion of specific substrates.
  • These changes in hepatic transporters may contribute to the altered disposition of substances in polycystic kidney disease.

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