Renal Transporter Expression Changes in Rodent Models of Nonalcoholic Steatohepatitis

Abstract

Inter-individual alterations to renal elimination processes can lead to adverse drug reactions. Nonalcoholic steatohepatitis (NASH) is known to alter hepatic drug transport but may also affect renal transporters as well. This study investigates renal physiological changes in rodent models of NASH for identification of a model that recapitulates human alterations. Rats on methionine and choline deficient (MCD), atherogenic (Athero) or control; Leprdb/db mice on MCD (db/db); C57BL/6J mice on fast food with thioacetamide (FFDTH), American lifestyle induced obesity syndrome (ALIOS) or control diet were used to characterize hepatic and renal pathology, clinical chemistry, and the transcriptional and translational expression of drug transporters by RT-qPCR and surrogate peptide LC-MS/MS, respectively. Hepatic pathology confirms development of NASH while renal pathology demonstrates no lesions except mild lipid accumulation in ALIOS. MCD, Athero and ALIOS exhibit an increase in blood urea nitrogen while all models, except Athero, demonstrate a decrease in GFR. There is a significant decrease in protein expression for renal basolateral uptake transporters, OCT3 and OATP4C1, for mouse models (from 1.97, 0.67 to 1.17, 0.35 db/db; 1.43, 0.27 FFDTH; 1.50, 0.34 ALIOS pmol/mg protein, respectively) but neither rat model. Similarly, renal apical uptake transporters, OAT5 and OATP1A1, exhibit a significant decrease in mouse models (from 4.59, 0.69 to 0.45, 0.02 db/db; 1.59, 0.21 FFDTH; 2.83, 0.36 ALIOS pmol/mg protein, respectively) but a significant increase of OAT5 in MCD (1.67 to 4.17 pmol/mg protein). Renal apical efflux transporters elicit a variety of significant changes in protein expression including an increase of MRP2 in MCD (0.17 to 0.30 pmol/mg protein), decrease of BCRP in db/db and ALIOS (from 0.25 to 0.14, 0.13 pmol/mg protein, respectively) and a decrease of MRP4 in mouse models (from 0.87 to 0.34 db/db; 0.29 FFDTH; 0.18 ALIOS pmol/mg protein). The only significant change in renal basolateral efflux transporters is a decrease in MRP3 protein in MCD and Athero (from 2.71 to 1.53, 1.68 pmol/mg protein, respectively). These data suggest variations in renal physiology are elicited by NASH in a range of rodent models. This demonstrates the potential variability in renal elimination of drugs during NASH and provides a resource to identify the appropriate model for future studies.