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