hURAT1 Transgenic Mouse Model for Evaluating Targeted Urate-Lowering Agents

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.