A stable liver-specific urate oxidase gene knockout hyperuricemia mouse model finds activated hepatic de novo purine biosynthesis and urate nephropathy

Lei Pang; Ningning Liang; Changgui Li; Tony R Merriman; Hui Zhang; Fei Yan; Wenyan Sun; Rui Li; Xiaomei Xue; Zhen Liu; Can Wang; Xiaoyu Cheng; Shiting Chen; Huiyong Yin; Nicola Dalbeth; Xuan Yuan

doi:10.1016/j.bbadis.2023.167009

A stable liver-specific urate oxidase gene knockout hyperuricemia mouse model finds activated hepatic de novo purine biosynthesis and urate nephropathy

Biochim Biophys Acta Mol Basis Dis. 2024 Mar;1870(3):167009. doi: 10.1016/j.bbadis.2023.167009. Epub 2024 Jan 17.

Authors

Lei Pang¹, Ningning Liang², Changgui Li¹, Tony R Merriman³, Hui Zhang⁴, Fei Yan⁵, Wenyan Sun⁵, Rui Li⁶, Xiaomei Xue⁵, Zhen Liu⁵, Can Wang⁵, Xiaoyu Cheng⁵, Shiting Chen², Huiyong Yin⁷, Nicola Dalbeth⁸, Xuan Yuan⁹

Affiliations

¹ Institute of Metabolic Diseases, Qingdao University, Qingdao, China; Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, Qingdao, China.
² CAS Key Laboratory of Nutrition, Metabolism, and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China, University of Chinese Academy of Sciences, Beijing, China.
³ Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, AL, United States.
⁴ Institute of Metabolic Diseases, Qingdao University, Qingdao, China.
⁵ Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, Qingdao, China.
⁶ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁷ CAS Key Laboratory of Nutrition, Metabolism, and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China, University of Chinese Academy of Sciences, Beijing, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Medicine, State Key Laboratory of Marine Pollution (SKLMP), The Shenzhen Research Institute, City University of Hong Kong, Hong Kong, China. Electronic address: hyyin@sinh.ac.cn.
⁸ Department of Medicine, University of Auckland, Auckland, New Zealand. Electronic address: n.dalbeth@auckland.ac.nz.
⁹ Institute of Metabolic Diseases, Qingdao University, Qingdao, China; Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, Qingdao, China. Electronic address: xyuan226@qdu.edu.cn.

PMID: 38237409
DOI: 10.1016/j.bbadis.2023.167009

Abstract

Urate oxidase (Uox)-deficient mice could be an optimal animal model to study hyperuricemia and associated disorders. We develop a liver-specific conditional knockout Uox-deficient (Uox^CKO) mouse using the Cre/loxP gene targeting system. These Uox^CKO mice spontaneously developed hyperuricemia with accumulated serum urate metabolites. Blocking urate degradation, the Uox^CKO mice showed significant de novo purine biosynthesis (DNPB) in the liver along with amidophosphoribosyltransferase (Ppat). Pegloticase and allopurinol reversed the elevated serum urate (SU) levels in Uox^CKO mice and suppressed the Ppat up-regulation. Although urate nephropathy occurred in 30-week-old Uox^CKO mice, 90 % of Uox-deficient mice had a normal lifespan without pronounced urate transport abnormality. Thus, Uox^CKO mice are a stable model of human hyperuricemia. Activated DNPB in the Uox^CKO mice provides new insights into hyperuricemia, suggesting increased SU influences purine synthesis.

Keywords: Hyperuricemia mouse model; Urate nephropathy; Urate synthesis; Uricase-deficiency; de novo purine biosynthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Gene Knockout Techniques
Humans
Hyperuricemia* / genetics
Kidney Diseases* / genetics
Liver / metabolism
Mice
Mice, Knockout
Urate Oxidase / genetics
Urate Oxidase / metabolism
Uric Acid / metabolism

Substances

Uric Acid
Urate Oxidase