Renal xenobiotic transporter expression is altered in multiple experimental models of nonalcoholic steatohepatitis

Mark J Canet; Rhiannon N Hardwick; April D Lake; Anika L Dzierlenga; John D Clarke; Michael J Goedken; Nathan J Cherrington

doi:10.1124/dmd.114.060574

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Renal xenobiotic transporter expression is altered in multiple experimental models of nonalcoholic steatohepatitis

Journal article

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Renal xenobiotic transporter expression is altered in multiple experimental models of nonalcoholic steatohepatitis

Mark J Canet, Rhiannon N Hardwick, April D Lake, Anika L Dzierlenga, John D Clarke, Michael J Goedken and Nathan J Cherrington

Drug metabolism and disposition, Vol.43(2), pp.266-272

02/2015

DOI: https://doi.org/10.1124/dmd.114.060574

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https://hdl.handle.net/2376/110785

PMCID: PMC4293398

PMID: 25488932

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Abstract

Non-alcoholic Fatty Liver Disease - pathology

Organic Anion Transporters, Sodium-Independent - genetics

Liver - pathology

Kidney - pathology

Male

Gene Expression Profiling

RNA, Messenger - metabolism

Kidney - metabolism

Protein Isoforms - metabolism

Mice, Mutant Strains

Organic Anion Transporters, Sodium-Independent - metabolism

Rats, Mutant Strains

Multidrug Resistance-Associated Proteins - genetics

Disease Models, Animal

Reproducibility of Results

Organic Cation Transport Proteins - metabolism

Mice, Inbred C57BL

Gene Expression Regulation

Non-alcoholic Fatty Liver Disease - metabolism

Rats, Sprague-Dawley

Animals

ATP Binding Cassette Transporter, Sub-Family B - metabolism

Organic Cation Transport Proteins - genetics

ATP Binding Cassette Transporter, Sub-Family B - genetics

Multidrug Resistance-Associated Proteins - metabolism

Protein Isoforms - genetics

Nonalcoholic fatty liver disease is the most common chronic liver disease, which can progress to nonalcoholic steatohepatitis (NASH). Previous investigations demonstrated alterations in the expression and activity of hepatic drug transporters in NASH. Moreover, studies using rodent models of cholestasis suggest that compensatory changes in kidney transporter expression occur to facilitate renal excretion during states of hepatic stress; however, little information is currently known regarding extrahepatic regulation of drug transporters in NASH. The purpose of the current study was to investigate the possibility of renal drug transporter regulation in NASH across multiple experimental rodent models. Both rat and mouse NASH models were used in this investigation and include: the methionine and choline-deficient (MCD) diet, atherogenic diet, fa/fa rat, ob/ob and db/db mice. Histologic and pathologic evaluations confirmed that the MCD and atherogenic rats as well as the ob/ob and db/db mice all developed NASH. In contrast, the fa/fa rats did not develop NASH but did develop extensive renal injury compared with the other models. Renal mRNA and protein analyses of xenobiotic transporters suggest that compensatory changes occur in NASH to favor increased xenobiotic secretion. Specifically, both apical efflux and basolateral uptake transporters are induced, whereas apical uptake transporter expression is repressed. These results suggest that NASH may alter the expression and potentially function of renal drug transporters, thereby impacting drug elimination mechanisms in the kidney.

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Title: Renal xenobiotic transporter expression is altered in multiple experimental models of nonalcoholic steatohepatitis
Creators: Mark J Canet - University of Arizona, Department of Pharmacology and Toxicology, Tucson, Arizona (M.J.C., R.N.H., A.D.L., A.L.D., J.D.C., N.J.C.); and Rutgers University, Office of Translational Science, New Brunswick, New Jersey (M.J.G.)
Rhiannon N Hardwick - University of Arizona, Department of Pharmacology and Toxicology, Tucson, Arizona (M.J.C., R.N.H., A.D.L., A.L.D., J.D.C., N.J.C.); and Rutgers University, Office of Translational Science, New Brunswick, New Jersey (M.J.G.)
April D Lake - University of Arizona, Department of Pharmacology and Toxicology, Tucson, Arizona (M.J.C., R.N.H., A.D.L., A.L.D., J.D.C., N.J.C.); and Rutgers University, Office of Translational Science, New Brunswick, New Jersey (M.J.G.)
Anika L Dzierlenga - University of Arizona, Department of Pharmacology and Toxicology, Tucson, Arizona (M.J.C., R.N.H., A.D.L., A.L.D., J.D.C., N.J.C.); and Rutgers University, Office of Translational Science, New Brunswick, New Jersey (M.J.G.)
John D Clarke - University of Arizona, Department of Pharmacology and Toxicology, Tucson, Arizona (M.J.C., R.N.H., A.D.L., A.L.D., J.D.C., N.J.C.); and Rutgers University, Office of Translational Science, New Brunswick, New Jersey (M.J.G.)
Michael J Goedken - University of Arizona, Department of Pharmacology and Toxicology, Tucson, Arizona (M.J.C., R.N.H., A.D.L., A.L.D., J.D.C., N.J.C.); and Rutgers University, Office of Translational Science, New Brunswick, New Jersey (M.J.G.)
Nathan J Cherrington - University of Arizona, Department of Pharmacology and Toxicology, Tucson, Arizona (M.J.C., R.N.H., A.D.L., A.L.D., J.D.C., N.J.C.); and Rutgers University, Office of Translational Science, New Brunswick, New Jersey (M.J.G.) cherrington@pharmacy.arizona.edu
Publication Details: Drug metabolism and disposition, Vol.43(2), pp.266-272
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: R01 AI083927 / NIAID NIH HHS T32 ES007091 / NIEHS NIH HHS P30-ES006694 / NIEHS NIH HHS ES007091 / NIEHS NIH HHS R01 HD062489 / NICHD NIH HHS P30 ES006694 / NIEHS NIH HHS R01-HD062489 / NICHD NIH HHS R01-AI083927 / NIAID NIH HHS
Identifiers: 99900547391401842
Language: English
Resource Type: Journal article