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Multidrug resistance-associated protein 4 is up-regulated in liver but down-regulated in kidney in obstructive

Gerald U Denk1, Carol J Soroka, Yasuaki Takeyama

  • 1Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA.

Journal of Hepatology
|March 20, 2004
PubMed
Abstract

Insights

Obstructive cholestasis upregulates multidrug resistance-associated protein 4 (Mrp4) protein in rat livers but downregulates it in kidneys. This suggests posttranscriptional regulation of Mrp4 expression.

Area of Science:

  • Hepatology and Nephrology
  • Drug Transporter Research
  • Biliary System Physiology

Background:

  • Multidrug resistance-associated protein 4 (Mrp4, ABCC4) is involved in transporting cyclic nucleotides, antivirals, and bile acids.
  • Previous studies indicated increased Mrp4 expression in farnesyl/bile acid receptor knockout mice.

Purpose of the Study:

  • To investigate the expression and function of Mrp4 in rat liver and kidney during obstructive cholestasis.
  • To elucidate the regulatory mechanisms of Mrp4 in cholestasis.

Main Methods:

  • Male Sprague-Dawley rats underwent bile duct ligation (BDL) or sham surgery.
  • Tissue analysis included Western blot, RT-PCR, and immunohistochemistry at 3, 7, and 14 days post-surgery.
  • Plasma and urine cyclic adenosine monophosphate levels were measured.

Main Results:

  • Hepatic Mrp4 protein expression increased over seven-fold 14 days after BDL (P < 0.05).
  • Renal Mrp4 protein expression decreased to 26% of controls in 14-day BDL rats (P < 0.005).
  • Mrp4 mRNA levels showed no significant changes in liver or kidney post-BDL, while plasma and urine cyclic AMP increased.

Conclusions:

  • Obstructive cholestasis induces progressive hepatic Mrp4 protein upregulation and renal downregulation in rats.
  • The dissociation between Mrp4 protein and mRNA levels suggests posttranscriptional regulation is key in BDL-induced cholestasis.

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