Expression and function of P-glycoprotein in rats with glycerol-induced acute renal failure

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Abstract

The effect of glycerol-induced acute renal failure on P-glycoprotein expression and function was evaluated in rats. The in vivo function of P-glycoprotein was evaluated by measuring renal secretory and biliary clearance and brain distribution of rhodamine 123 (Rho-123), a P-glycoprotein substrate, under a steady-state plasma concentration. In acute renal failure rats, the P-glycoprotein level increased 2.5-fold in the kidney, but not in the liver and brain. In contrast, P-glycoprotein function in these tissues was suppressed. Interestingly, not only the renal but also the biliary clearance of Rho-123 was correlated with the glomerular filtration rate. In Caco-2 cells, plasma from renal failure rats exhibited a greater inhibitory effect on P-glycoprotein-mediated transport of Rho-123 than did plasma from control rats. In conclusion, P-glycoprotein function was systemically suppressed in acute renal failure, even though the level of P-glycoprotein remained unchanged or rather increased. This may be due to the accumulation of some endogenous P-glycoprotein substrates/modulators in the plasma in disease states.

Introduction

The kidney and liver are important organs in the detoxification of xenobiotics, and dysfunction of these organs exerts a large influence on the pharmacokinetics of drugs not only at the target injury organ, but also at other organs. For example, acute renal failure induced by glycerol or uranyl nitrate reduces the hepato-biliary transport of some drugs, modulates the distribution of drugs into the central nervous system and affects the activity of various hepatic microsomal enzymes Bowmer and Yates, 1984, Yeung, 1991, Zurovsky, 1993, Naora et al., 1999, besides suppressing kidney function including the glomerular filtration and tubular secretion of organic anions and cations Hori et al., 1985, Lin and Lin, 1988, Inui et al., 1989, Zurovsky, 1993. The mechanism of this systemic alteration of the host defense system in acute renal failure, however, is not yet fully understood.

P-glycoprotein, an ATP-dependent efflux pump, is expressed widely in normal tissues, including brush border membrane of renal proximal tubules, biliary canalicular membranes of hepatocytes and capillary endothelial cells of the brain Thiebaut et al., 1987, Cordon-Cardo et al., 1989. This protein transports a variety of structurally and pharmacologically unrelated hydrophobic compounds and plays an important role in the excretion of exogenous and endogenous P-glycoprotein substrates to prevent the accumulation of these compounds in tissues Thiebaut et al., 1987, Lee et al., 1994, Scala et al., 1997, Kajikawa et al., 1999, Kajikawa et al., 2000. Recently, we reported a marked reduction of the renal secretory clearance of rhodamine 123 (Rho-123), a P-glycoprotein substrate, in glycerol-induced acute renal failure rats, indicating the suppression of P-glycoprotein-mediated tubular secretion (Kunihara et al., 1998). The pathogenic mechanisms underlying glycerol-induced acute renal failure include ischemic injury, tubular nephrotoxicity caused by myoglobin, and the renal action of cytokines released after rhabdomyolysis Wolfert and Oken, 1989, Vexler et al., 1996. Rho-123 has been used as a probe to assess P-glycoprotein function in various cell lines and to examine whether a test compound is a P-glycoprotein inhibitor or not Lee et al., 1994, Scala et al., 1997.

In the present study, the effect of glycerol-induced acute renal failure on P-glycoprotein expression and its in vivo function in the liver, kidney and brain was evaluated over 7 days after glycerol injection. In addition, the possible mechanism underlying the systemic modulation of P-glycoprotein function in acute renal failure was examined from the point of view of the involvement of endogenous P-glycoprotein substrates/modulators.

Section snippets

Materials

Rho-123 was obtained from Kanto Chemical (Tokyo, Japan). Cyclosporin A was kindly supplied by Novartis (Tokyo, Japan). A monoclonal antibody for P-glycoprotein, C219, was from Signet Laboratories (MA, USA) and a secondary antibody, peroxidase-labelled affinity-purified antibody to mouse immunoglobulin G (H+L), was from Kirkegaard & Perry Laboratories (MD, USA). All other chemicals used were of the highest purity available.

Animal treatment

Experiments with animals were performed in accordance with the “Guide for

Biochemical parameters of acute renal failure rats

Induction of acute renal failure in rats after treatment with glycerol was evaluated by measuring some biochemical parameters (Table 1). The glycerol-treated rats showed significantly higher BUN values on days 1 and 3 and lower glomerular filtration rate values over 5 days than did the control rats. The plasma glutamic oxaloacetic transaminase and glutamic pyruvic transaminase levels increased only on the first day of the glycerol-induced acute renal failure. These biochemical parameters

Discussion

The present study was carried out to examine the effect of acute renal failure on P-glycoprotein level and in vivo P-glycoprotein function in rats. As to the effect of glycerol-induced acute renal failure on in vivo P-glycoprotein function, we previously demonstrated that the renal tubular secretion of Rho-123 was greatly suppressed in acute renal failure rats. In the present study, we further examined the effect of acute renal failure on in vivo P-glycoprotein function systemically, not only

Acknowledgements

This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture in Japan and by a grant from the Naito Foundation.

References (33)

  • C. Cordon-Cardo et al.

    Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood–brain barrier sites

    Proc. Natl. Acad. Sci. U. S. A.

    (1989)
  • R. Hori et al.

    Transport of p-aminohippurate, tetraethylammonium and d-glucose in renal brush border membranes from rats with acute renal failure

    J. Pharmacol. Exp. Ther.

    (1985)
  • K. Inui et al.

    Decreased transport of p-aminohippurate in renal basolateral membranes isolated from rats with acute renal failure

    Pharm. Res.

    (1989)
  • T. Kajikawa et al.

    Role of P-glycoprotein in distribution of rhodamine 123 into aqueous humor in rabbits

    Curr. Eye Res.

    (1999)
  • T. Kajikawa et al.

    Role of P-glycoprotein in ocular clearance of rhodamine 123 in rabbits

    Pharm. Res.

    (2000)
  • M. Kunihara et al.

    Renal excretion of rhodamine 123, a P-glycoprotein substrate, in rats with glycerol-induced acute renal failure

    J. Pharm. Pharmacol.

    (1998)
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