Neutral aminoaciduria in cystathionine β-synthase-deficient mice; an animal model of homocystinuria.
The kidney is one of the major loci for the expression of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH). While CBS-deficient (Cbs(-/-)) mice display homocysteinemia/methioninemia and severe growth retardation, and rarely survive beyond the first 4 wk, CTH-deficient (Cth(-/-)) mice show homocysteinemia/cystathioninemia but develop with no apparent abnormality. This study examined renal amino acid reabsorption in those mice. Although both 2-wk-old Cbs(-/-) and Cth(-/-) mice had normal renal architecture, their serum/urinary amino acid profiles largely differed from wild-type mice. The most striking feature was marked accumulation of Met and cystathionine in serum/urine/kidney samples of Cbs(-/-) and Cth(-/-) mice, respectively. Levels of some neutral amino acids (Val, Leu, Ile, and Tyr) that were not elevated in Cbs(-/-) serum were highly elevated in Cbs(-/-) urine, and urinary excretion of other neutral amino acids (except Met) was much higher than expected from their serum levels, demonstrating neutral aminoaciduria in Cbs(-/-) (not Cth(-/-)) mice. Because the bulk of neutral amino acids is absorbed via a B(0)AT1 transporter and Met has the highest substrate affinity for B(0)AT1 than other neutral amino acids, hypermethioninemia may cause hyperexcretion of neutral amino acids.
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo, Japan; Department of Immunology, Akita University Graduate School of Medicine, Akita, Japan; and.
Noriyuki
N
Akahoshi
Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan.
Shotaro
S
Kamata
Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan.
Masashi
M
Kubota
Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo, Japan;
Takako
T
Hishiki
Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo, Japan;
Yoshiko
Y
Nagahata
Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo, Japan;
Tomomi
T
Matsuura
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan;
Chiho
C
Yamazaki
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan;
Yuka
Y
Yoshida
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan;
Hidenori
H
Yamada
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan;
Yasuki
Y
Ishizaki
Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo, Japan;
Makoto
M
Suematsu
Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan.
Tadashi
T
Kasahara
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan; Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan isao-ishii@umin.ac.jp.
Isao
I
Ishii
D021542:Amino Acids, Neutral / Q000378:metabolism*; D000818:Animals; D015897:Comorbidity; D003540:Cystathionine / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006712:Homocystinuria / Q000453:epidemiology* / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000473:pathology; D008297:Male; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000608:Renal Aminoacidurias / Q000453:epidemiology* / Q000378:metabolism*
D021542:Amino Acids, Neutral; D003540:Cystathionine; D008715:Methionine; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase
amino acid reabsorption; amino acid transporter; cystathionine γ-lyase; homocystinuria; transsulfuration