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An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
Representative Rodent Models for Renal Transporter Alterations in Human Nonalcoholic Steatohepatitis
Kayla L Frost1, Joseph L Jilek1, Erica L Toth1
1College of Pharmacy, Department of Pharmacology & Toxicology (K.L.F., J.L.J., E.L.T., N.J.C.) and College of Medicine, Department of Physiology (S.H.W.), The University of Arizona, Tucson, Arizona and Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey (M.J.G.).
Abstract:
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 liquid chromatography-coupled mass spectrometry (LC-MS/MS) on renal biopsies from NASH patients was used for concordance analysis with rodent models, including methionine/choline deficient (MCD), atherogenic (Athero), or control rats and 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 glomerular filtration rate (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 that the mouse models are comparable to human for these specific transport processes. These data suggest that 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.
Insights
Nonalcoholic steatohepatitis (NASH) alters kidney transporters. This study identified specific rodent models that mimic human renal transporter changes, aiding future drug safety studies.
Area of Science:
- Pharmacology and Toxicology
- Nephrology
- Hepatology
Background:
- Adverse drug reactions can arise from altered kidney elimination, including glomerular filtration and tubular secretion.
- Nonalcoholic steatohepatitis (NASH) is known to affect liver xenobiotic metabolism, but its impact on renal transporters was previously unclear.
Purpose of the Study:
- To investigate renal transporter alterations in rodent models of NASH.
- To identify NASH rodent models that accurately recapitulate human renal transporter changes.
- To enable appropriate model selection for future pharmacokinetic studies and prevent adverse drug reactions.
Main Methods:
- Quantitative protein expression analysis using liquid chromatography-coupled mass spectrometry (LC-MS/MS) on renal biopsies from NASH patients and rodent models.
- Concordance analysis of renal transporter expression and glomerular filtration rate (GFR) between human NASH patients and various rodent models (MCD, Athero, db/db, FFDTH, ALIOS).
- Evaluation of specific transporters including Organic Anion Transporter 3 (OAT3) and OAT5.
Main Results:
- Rodent models db/db, FFDTH, and ALIOS demonstrated decreased glomerular filtration rate (GFR), similar to NASH patients.
- The FFDTH model uniquely mirrored human changes in Organic Anion Transporter 3 (OAT3) expression.
- Significant decreases in OAT5 were observed in db/db, FFDTH, and ALIOS models, while MCD models showed an increase, indicating comparability to human OAT5 alterations.
Conclusions:
- Nonalcoholic steatohepatitis induces variations in rodent renal transporter expression.
- Specific rodent models (db/db, FFDTH, ALIOS) effectively recapitulate human renal transporter alterations seen in NASH.
- This research facilitates the selection of suitable models for transporter-specific pharmacokinetic studies, crucial for predicting and preventing drug-induced adverse events.
