You have accessJournal of UrologyStone Disease: Basic Research & Pathophysiology I (PD04)1 Apr 2020PD04-05 TARGETING HYDROXYPROLINE DEHYDROGENASE AS A POTENTIAL THERAPY FOR TYPE 2 PRIMARY HYPEROXALURIA John Knight, Dean Assimos, Ross Holmes, Kyle Wood*, and Todd Lowther John KnightJohn Knight More articles by this author , Dean AssimosDean Assimos More articles by this author , Ross HolmesRoss Holmes More articles by this author , Kyle Wood*Kyle Wood* More articles by this author , and Todd LowtherTodd Lowther More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000824.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients with type 2 primary hyperoxaluria (PH2) have a defect in Glyoxylate reductase (GR) resulting in excessive urinary oxalate excretion. These patients do not respond to pyridoxine therapy and some may require combined liver/renal transplantation. We have recently reported that the metabolism of trans-4-hydroxy-L-proline (Hyp), an amino acid derived predominantly from collagen metabolism, is a significant source of oxalate production in individuals with PH2. Hydroxyproline dehydrogenase (HYPDH) is the initial enzyme in the metabolism of Hyp to glyoxylate, the immediate precursor to oxalate. Herein, we describe the phenotypes of the Prodh2 knock out (KO), a HYPDH knock out mouse model, a GR KO (Grhpr) which mimics PH2, and a double KO mouse, Prodh2 /Grhpr. METHODS: These KO mice were created using CRISPR/Cas methodology. Male mice, 12-16 weeks of age, were singly housed in metabolic cages for collection of three consecutive 24-hour urines. Mice had free access to water and a calcium-deficient, high-sucrose basal diet to which calcium chloride was added at 5 mg per gram dry diet. This custom diet contains a very low background oxalate content (12.9 ± 1.1 µg oxalate per gram diet) and is devoid of Hyp. The diet contains 19.6% protein, 57.7% carbohydrate, 6.6% fat, and 10.3% cellulose. Ion chromatography coupled with mass spectroscopy was used. RESULTS: In the HYPDH KO mice (n=9), the plasma Hyp and urinary Hyp excretion levels were significantly elevated as compared to WT animals (n=13); 760 ± 193 µM vs 14.7 ± 3.1 (p<0.001) and 808 ± 532 µg vs <19 µg (p<0.001), respectively. Prodh2 KO mice had an 18% lower urinary oxalate excretion as compared with WT mice (102 ± 4.1 vs 83.7 ± 3.7 µg/mg creatinine, p = 0.002) and a 20% lower urinary glycolate excretion (p = 0.014). Prodh2 /Grhpr KO mice (n=9) had reduced urinary oxalate excretion, 30% lower as compared to the Grhpr KO mice (n=8) (178 ± 9 vs 255 ± 16 µG/mg creatinine, p<0.003). CONCLUSIONS: Hydroxyproline dehydrogenase represents a promising therapeutic target for reducing urinary oxalate excretion in PH2 individuals. Source of Funding: NIH K08 DK 115833-01 A1 © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e80-e80 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information John Knight More articles by this author Dean Assimos More articles by this author Ross Holmes More articles by this author Kyle Wood* More articles by this author Todd Lowther More articles by this author Expand All Advertisement PDF downloadLoading ...