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J Am Soc Nephrol ; 33(2): 326-341, 2022 02.
Article in English | MEDLINE | ID: covidwho-2141035


BACKGROUND: Hereditary renal hypouricemia type 1 (RHUC1) is caused by URAT1/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced AKI (EIAKI). However, because there is no useful experimental RHUC1 animal model, the precise pathophysiologic mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity Urat1-Uox double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI and the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs). METHODS: The novel Urat1-Uox DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters. RESULTS: Urat1-Uox DKO mice had uricosuric effects and elevated levels of plasma creatinine and BUN as renal injury markers, and decreased creatinine clearance observed in a forced swimming test. In addition, Urat1-Uox DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na+-K+-ATPase protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI. CONCLUSIONS: Urat1-Uox DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1ß via NLRP3 inflammasome signaling and Na+-K+-ATPase dysfunction associated with excessive urinary urate excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI.

Acute Kidney Injury/drug therapy , Hypoxanthine Phosphoribosyltransferase/metabolism , Organic Anion Transporters/deficiency , Urate Oxidase/deficiency , Xanthine Dehydrogenase/antagonists & inhibitors , Acute Kidney Injury/etiology , Acute Kidney Injury/metabolism , Allopurinol/pharmacology , Animals , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Hypoxanthine Phosphoribosyltransferase/genetics , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Nitriles/pharmacology , Organic Anion Transporters/genetics , Physical Exertion , Pyridines/pharmacology , Renal Tubular Transport, Inborn Errors/drug therapy , Renal Tubular Transport, Inborn Errors/etiology , Renal Tubular Transport, Inborn Errors/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Urate Oxidase/genetics , Urinary Calculi/drug therapy , Urinary Calculi/etiology , Urinary Calculi/metabolism