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hURAT1 Transgenic Mouse Model for Evaluating Targeted Urate-Lowering Agents.

Weiyan Cai¹, Miyi Yang¹, Qinghe Zhao¹

¹Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.

International Journal of Rheumatic Diseases

|December 31, 2024

Summary

A new human URAT1 knock-in mouse model effectively mimics hyperuricemia and gout conditions. This model allows for preclinical evaluation of urate-lowering drugs targeting URAT1, advancing gout treatment research.

Keywords:

SLC22A12 URAT1 gout hyperuricemia transporter uric acid

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Area of Science:

Biochemistry
Pharmacology
Genetics

Background:

Urate transporter 1 (URAT1) is a key target for managing hyperuricemia and gout.
Existing research lacks non-primate animal models to test URAT1 inhibitors effectively.
A human URAT1 (hURAT1) transgenic knock-in (KI) mouse model was developed.

Purpose of the Study:

To establish a novel hURAT1 KI mouse model for evaluating uricosuric agents.
To characterize the pathogenesis associated with URAT1 in a preclinical setting.
To assess the efficacy of URAT1 inhibitors in a relevant animal model.

Main Methods:

Generation of hURAT1 transgenic mice using CRISPR/Cas9 knock-in technology.
Replacement of mouse Urat1 exon 1 with human SLC22A12 coding sequence.
Induction of hyperuricemia via hypoxanthine administration in hURAT1 KI mice.

Main Results:

hURAT1 protein was correctly localized to the kidney proximal tubule epithelium in KI mice.
Hypoxanthine challenge significantly elevated blood uric acid (UA) in hURAT1 KI mice compared to wild-type (WT).
The hURAT1 inhibitor benzbromarone effectively lowered elevated UA levels in hURAT1 KI mice, but not in WT mice.

Conclusions:

The developed hURAT1 KI mouse model is a valuable tool for preclinical assessment of gout treatments.
This model facilitates the study of human UA metabolic complexities.
It enables the evaluation of urate-lowering drugs targeting URAT1.