title: Renal xenobiotic transporter expression is altered in multiple experimental models of nonalcoholic steatohepatitis.
abstract: 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.
authors.affiliation: 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.).
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Canet
authors.affiliation: 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.).
authors.forename: Rhiannon N
authors.initials: RN
authors.lastname: Hardwick
authors.affiliation: 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.).
authors.forename: April D
authors.initials: AD
authors.lastname: Lake
authors.affiliation: 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.).
authors.forename: Anika L
authors.initials: AL
authors.lastname: Dzierlenga
authors.affiliation: 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.).
authors.forename: John D
authors.initials: JD
authors.lastname: Clarke
authors.affiliation: 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.).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goedken
authors.affiliation: 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.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Cherrington
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger