NDLI: Metabolism of $^{13}C_{5}-hydroxyproline$ in mouse models of Primary Hyperoxaluria and its inhibition by RNAi therapeutics targeting liver glycolate oxidase and hydroxyproline dehydrogenase☆

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Fargue, Sonia Guan, Zhengrong Liebow, Abigail Inscho, Edward W. Buchalski, Brianna Li, Xingsheng Querbes, William Holmes, Ross P. Knight, John Todd Lowther, W. Fitzgerald, Kevin
Description	Author Affiliation: Li X ( Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.); Knight J ( Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.); Fargue S ( Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.); Buchalski B ( Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.); Guan Z ( Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States.); Inscho EW ( Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States.); Liebow A ( Alnylam Pharmaceuticals, Cambridge, MA, United States.); Fitzgerald K ( Alnylam Pharmaceuticals, Cambridge, MA, United States.); Querbes W ( Alnylam Pharmaceuticals, Cambridge, MA, United States.); Todd Lowther W ( Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.); Holmes RP ( Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: rholmes@uab.edu.)
Abstract	Excessive endogenous oxalate synthesis can result in calcium oxalate kidney stone formation and renal failure. Hydroxyproline catabolism in the liver and kidney contributes to endogenous oxalate production in mammals. To quantify this contribution we have infused Wt mice, Agxt KO mice deficient in liver alanine:glyoxylate aminotransferase, and Grhpr KO mice deficient in glyoxylate reductase, with $^{13}$ C $_{5}$ -hydroxyproline. The contribution of hydroxyproline metabolism to urinary oxalate excretion in Wt mice was 22 ± 2%, 42 ± 8% in Agxt KO mice, and 36% ± 9% in Grhpr KO mice. To determine if blocking steps in hydroxyproline and glycolate metabolism would decrease urinary oxalate excretion, mice were injected with siRNA targeting the liver enzymes glycolate oxidase and hydroxyproline dehydrogenase. These siRNAs decreased the expression of both enzymes and reduced urinary oxalate excretion in Agxt KO mice, when compared to mice infused with a luciferase control preparation. These results suggest that siRNA approaches could be useful for decreasing the oxalate burden on the kidney in individuals with Primary Hyperoxaluria.
ISSN	00063002
Journal	Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Issue Number	2
Volume Number	1862
Language	English
Publisher	Elsevier
Publisher Date	2016-02-01
Publisher Place	Netherlands
Access Restriction	Open
Subject Keyword	Biochemistry
Content Type	Text
Resource Type	Article

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