Biochemical Pathways of 8-aminoguanine Production in Sprague-Dawley and Dahl Salt-sensitive Rats

Overview

Journal Biochem Pharmacol

Specialties Biochemistry
Pharmacology

Date 2022 May 13

PMID 35551915

Authors

Edwin K Jackson

Elizabeth V Menshikova

Vladimir B Ritov

Delbert G Gillespie

Zaichuan Mi

Affiliations

Soon will be listed here.

Abstract

Background: 8-Aminoguanine exerts natriuretic and antihypertensive activity. Whether and how "free" 8-aminoguanine exists in vivo is unclear. Because 8-nitroguanosine is naturally occurring, we tested the hypothesis that 8-aminoguanine can arise from: pathway 1, 8-nitroguanosine → 8-aminoguanosine → 8-aminoguanine; and pathway 2, 8-nitroguanosine → 8-nitroguanine → 8-aminoguanine.

Methods: 8-Aminoguanine biosynthesis was explored in rats using renal microdialysis, mass spectrometry and enzyme kinetics.

Results: In Sprague-Dawley rats, 8-nitroguanosine infusions increased kidney levels of 8-nitroguanine, 8-aminoguanosine and 8-aminoguanine; 8-nitroguanine infusions increased 8-aminoguanine. Purine nucleoside phosphorylase (PNPase) converted 8-nitroguanosine to 8-nitroguanine and 8-aminoguanosine to 8-aminoguanine. Forodesine (PNPase inhibitor) reduced metabolism of 8-nitroguanosine by pathway 2 and shunted metabolism of 8-nitroguanosine to 8-aminoguanosine. In Dahl salt-sensitive rats, 8-nitroguanosine infusions increased kidney levels of 8-nitroguanine, 8-aminoguanosine and 8-aminoguanine. These results indicate that both pathways 1 and 2 participate in the biosynthesis of 8-aminoguanine in Sprague-Dawley and Dahl rats. Endogenous 8-aminoguanine in kidneys and urine were elevated many-fold in Dahl, compared to Sprague-Dawley, rats. The increased levels of 8-aminoguanine in Dahl rats were not due to alterations in pathways 1 and 2 but were associated with increased urine levels of endogenous 8-nitroguanosine suggesting that the "upstream" production of 8-nitroguanosine was increased in Dahl rats. Dahl rats are known to have high levels of peroxynitrite, and peroxynitrite is known to nitrate guanosine in biomolecules. Here we confirm that a peroxynitrite donor increases kidney levels of 8-aminoguanine.

Conclusion: 8-Aminoguanine occurs naturally via two distinct pathways and kidney levels of 8-aminoguanine are increased in Dahl rats, likely due to increased production of 8-nitroguanosine, a by-product of peroxynitrite chemistry.

Citing Articles

8-Aminopurines: A Promising New Direction for Purine-Based Therapeutics.

Jackson E, Tofovic S, Chen Y, Birder L Hypertension. 2024; 81(12):2410-2414.

PMID: 39429198 PMC: 11578759. DOI: 10.1161/HYPERTENSIONAHA.124.21726.

8-Aminoguanine and its actions in the metabolic syndrome.

Jackson E, Gillespie D, Mi Z, Birder L, Tofovic S Sci Rep. 2024; 14(1):22652.

PMID: 39349636 PMC: 11442972. DOI: 10.1038/s41598-024-73159-4.

Oral 8-aminoguanine against age-related retinal degeneration.

Chen Y, Vats A, Xi Y, Wolf-Johnston A, Clinger O, Arbuckle R Res Sq. 2024; .

PMID: 38765984 PMC: 11100887. DOI: 10.21203/rs.3.rs-4022389/v1.

8-Aminopurines in the Cardiovascular and Renal Systems and Beyond.

Jackson E, Tofovic S, Chen Y, Birder L Hypertension. 2023; 80(11):2265-2279.

PMID: 37503660 PMC: 10592300. DOI: 10.1161/HYPERTENSIONAHA.123.20582.

References

Jackson E, Cheng D, Tofovic S, Mi Z . Endogenous adenosine contributes to renal sympathetic neurotransmission via postjunctional A1 receptor-mediated coincident signaling. Am J Physiol Renal Physiol. 2011; 302(4):F466-76. PMC: 3289416. DOI: 10.1152/ajprenal.00495.2011. View

Park E, Shigenaga M, Degan P, Korn T, Kitzler J, Wehr C . Assay of excised oxidative DNA lesions: isolation of 8-oxoguanine and its nucleoside derivatives from biological fluids with a monoclonal antibody column. Proc Natl Acad Sci U S A. 1992; 89(8):3375-9. PMC: 48870. DOI: 10.1073/pnas.89.8.3375. View

Zaki M, Akuta T, Akaike T . Nitric oxide-induced nitrative stress involved in microbial pathogenesis. J Pharmacol Sci. 2005; 98(2):117-29. DOI: 10.1254/jphs.crj05004x. View

Hu C, Chang Y, Chen J, Hsu Y, Chao M . Sensitive Detection of 8-Nitroguanine in DNA by Chemical Derivatization Coupled with Online Solid-Phase Extraction LC-MS/MS. Molecules. 2018; 23(3). PMC: 6017919. DOI: 10.3390/molecules23030605. View

Hu C, Chang Y, Hsu Y, Chen J, Wang T, Chao M . Comprehensive analysis of the formation and stability of peroxynitrite-derived 8-nitroguanine by LC-MS/MS: Strategy for the quantitative analysis of cellular 8-nitroguanine. Free Radic Biol Med. 2016; 101:348-355. DOI: 10.1016/j.freeradbiomed.2016.10.505. View

Kelly K, Plotkin Z, Dagher P . Guanosine supplementation reduces apoptosis and protects renal function in the setting of ischemic injury. J Clin Invest. 2001; 108(9):1291-8. PMC: 209442. DOI: 10.1172/JCI13018. View

Mori T, OConnor P, Abe M, Cowley Jr A . Enhanced superoxide production in renal outer medulla of Dahl salt-sensitive rats reduces nitric oxide tubular-vascular cross-talk. Hypertension. 2007; 49(6):1336-41. DOI: 10.1161/HYPERTENSIONAHA.106.085811. View

Chen H, Chang C, Chen Y . Hemoprotein-mediated reduction of nitrated DNA bases in the presence of reducing agents. Free Radic Biol Med. 2003; 34(2):254-68. DOI: 10.1016/s0891-5849(02)01246-7. View

Han F, Lillard S . In-situ sampling and separation of RNA from individual mammalian cells. Anal Chem. 2000; 72(17):4073-9. DOI: 10.1021/ac000428g. View

10.

Jackson E, Mi Z, Kleyman T, Cheng D . 8-Aminoguanine Induces Diuresis, Natriuresis, and Glucosuria by Inhibiting Purine Nucleoside Phosphorylase and Reduces Potassium Excretion by Inhibiting Rac1. J Am Heart Assoc. 2019; 7(21):e010085. PMC: 6404173. DOI: 10.1161/JAHA.118.010085. View

11.

Bzowska A, Kulikowska E, SHUGAR D . Purine nucleoside phosphorylases: properties, functions, and clinical aspects. Pharmacol Ther. 2001; 88(3):349-425. DOI: 10.1016/s0163-7258(00)00097-8. View

12.

Birder L, Wolf-Johnston A, Wein A, Cheng F, Grove-Sullivan M, Kanai A . Purine nucleoside phosphorylase inhibition ameliorates age-associated lower urinary tract dysfunctions. JCI Insight. 2020; 5(20). PMC: 7605521. DOI: 10.1172/jci.insight.140109. View

13.

Sodum R, Nie G, Fiala E . 8-Aminoguanine: a base modification produced in rat liver nucleic acids by the hepatocarcinogen 2-nitropropane. Chem Res Toxicol. 1993; 6(3):269-76. DOI: 10.1021/tx00033a004. View

14.

Ahmed K, Sawa T, Ihara H, Kasamatsu S, Yoshitake J, Rahaman M . Regulation by mitochondrial superoxide and NADPH oxidase of cellular formation of nitrated cyclic GMP: potential implications for ROS signalling. Biochem J. 2011; 441(2):719-30. DOI: 10.1042/BJ20111130. View

15.

Jackson E, Gillespie D, Mi Z, Cheng D . Adenosine Receptors Influence Hypertension in Dahl Salt-Sensitive Rats: Dependence on Receptor Subtype, Salt Diet, and Sex. Hypertension. 2018; 72(2):511-521. PMC: 6053282. DOI: 10.1161/HYPERTENSIONAHA.117.10765. View

16.

Kohr M, Davis J, Ziolo M . Peroxynitrite Increases Protein Phosphatase Activity and Promotes the Interaction of Phospholamban with Protein Phosphatase 2a in the Myocardium. Nitric Oxide. 2011; 20(3):217-221. PMC: 2909675. DOI: 10.1016/j.niox.2009.01.003. View

17.

Jackson E, Menshikova E, Mi Z, Verrier J, Bansal R, Janesko-Feldman K . Renal 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase Is an Important Determinant of AKI Severity after Ischemia-Reperfusion. J Am Soc Nephrol. 2015; 27(7):2069-81. PMC: 4926972. DOI: 10.1681/ASN.2015040397. View

18.

Zhou M, Schulman I, Pagano P, Jaimes E, Raij L . Reduced NAD(P)H oxidase in low renin hypertension: link among angiotensin II, atherogenesis, and blood pressure. Hypertension. 2005; 47(1):81-6. DOI: 10.1161/01.HYP.0000197182.65554.c7. View

19.

Chen H, Chang C . Lipoyl dehydrogenase catalyzes reduction of nitrated DNA and protein adducts using dihydrolipoic acid or ubiquinol as the cofactor. Chem Biol Interact. 2002; 140(3):199-213. DOI: 10.1016/s0009-2797(02)00019-4. View

20.

Lam P, Mistry V, Marczylo T, Konje J, Evans M, Cooke M . Rapid measurement of 8-oxo-7,8-dihydro-2'-deoxyguanosine in human biological matrices using ultra-high-performance liquid chromatography-tandem mass spectrometry. Free Radic Biol Med. 2012; 52(10):2057-63. PMC: 3404459. DOI: 10.1016/j.freeradbiomed.2012.03.004. View