Increased plasma and tissue guanidino compounds in a mouse model of hyperargininemia.
In humans, arginase I (AI)-deficiency results in hyperargininemia, a metabolic disorder with symptoms of progressive neurological and intellectual impairment, spasticity, persistent growth retardation, and episodic hyperammonemia. A deficiency of arginase II (AII) has never been detected and the clinical disorder, if any, associated with its deficiency has not been defined. Since the spasticity and paucity of hyperammonemic crises seen in human AI-deficient patients are not features of the other urea cycle disorders, the likelihood of ammonia as the main neuropathogenic agent becomes extremely low, and the modest elevations of arginine seen in the brains of our mouse model of hyperargininemia make it an unlikely candidate as well. Specific guanidino compounds, direct or indirect metabolites of arginine, are elevated in the blood of patients with uremia. Other guanidino compounds are also increased in plasma and cerebrospinal fluid of hyperargininemic patients making them plausible as neurotoxins in these disorders. We analyzed several guanidino compounds in our arginase single and double knockout animals and found that alpha-keto-delta-guanidinovaleric acid, alpha-N-acetylarginine, and argininic acid were increased in the brain tissue from the AI knockout and double knockout animals. Several compounds were also increased in the plasma, liver, and kidneys. This is the first time that several of the guanidino compounds have been shown to be elevated in the brain tissue of an arginase-deficient mammal, and it further supports their possible role as the neuropathogenic agents responsible for the complications seen in arginase deficiency.
Deignan
Joshua L
JL
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA.
Marescau
Bart
B
Livesay
Justin C
JC
Iyer
Ramaswamy K
RK
De Deyn
Peter P
PP
Cederbaum
Stephen D
SD
Grody
Wayne W
WW
D000818:Animals; D001119:Arginase / Q000235:genetics; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D006146:Guanidines / Q000097:blood* / Q000378:metabolism; D006801:Humans; D020162:Hyperargininemia / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D006146:Guanidines; C481673:Arg2 protein, mouse; D001119:Arginase