Representative Rodent Models for Renal Transporter Alterations in Human Nonalcoholic Steatohepatitis.

Alterations in renal elimination processes of glomerular filtration and active tubular secretion by renal transporters can result in adverse drug reactions. Nonalcoholic steatohepatitis (NASH) alters hepatic transporter expression and xenobiotic elimination, but until recently, renal transporter alterations in NASH were unknown. This study investigates renal transporter changes in rodent models of NASH to identify a model that recapitulates human alterations. Quantitative protein expression by surrogate peptide LCMS/MS on renal biopsies from NASH patients were used for concordance analysis with rodent models, including methionine-choline-deficient (MCD), atherogenic (Athero) or control rats; Leprdb/db MCD (db/db), C57BL/6J fast food thioacetamide (FFDTH), American lifestyle induced obesity syndrome (ALIOS), or control mice. Demonstrating clinical similarity to NASH patients, db/db, FFDTH, and ALIOS showed decreases in GFR by 76, 28, and 24%. Organic anion transporter 3 (OAT3) showed an upward trend in all models except the FFDTH (from 3.20 to 2.39 pmol/mg protein), making the latter the only model to represent human OAT3 changes. OAT5, a functional ortholog of human OAT4, significantly decreased in db/db, FFDTH, and ALIOS (from 4.59 to 0.45, 1.59, and 2.83 pmol/mg protein, respectively), but significantly increased for MCD (1.67 to 4.17 pmol/mg protein), suggesting the mouse models are comparable to human for these specific transport processes. These data suggest variations in rodent renal transporter expression are elicited by NASH and the concordance analysis enables appropriate model selection for future pharmacokinetic studies based on transporter specificity. These models provide a valuable resource to extrapolate the consequences of human variability in renal drug elimination. Significance Statement Rodent models of nonalcoholic steatohepatitis that recapitulate human renal transporter alterations are identified for future transporter specific pharmacokinetic studies to facilitate the prevention of adverse drug reactions due to human variability.