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.
Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan.
Am J Physiol Renal Physiol. 2014 Jun 15;306(12):F1462-76. doi: 10.1152/ajprenal.00623.2013. Epub 2014 Apr 23.
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.
肾脏是胱硫醚β-合酶（CBS）和胱硫醚γ-裂合酶（CTH）表达的主要部位之一。CBS 缺陷（Cbs(-/-)）小鼠表现出血同型半胱氨酸/蛋氨酸血症和严重的生长迟缓，很少能存活超过第 4 周，而 CTH 缺陷（Cth(-/-)）小鼠表现出血同型半胱氨酸/胱硫醚血症，但发育正常，没有明显异常。本研究检查了这些小鼠的肾脏氨基酸重吸收。尽管 2 周龄的 Cbs(-/-)和 Cth(-/-)小鼠具有正常的肾脏结构，但它们的血清/尿氨基酸谱与野生型小鼠有很大的不同。最显著的特征是 Cbs(-/-)和 Cth(-/-)小鼠的血清/尿液/肾脏样本中分别明显积累了 Met 和胱硫醚。一些中性氨基酸（Val、Leu、Ile 和 Tyr）的水平在 Cbs(-/-)血清中没有升高，但在 Cbs(-/-)尿液中高度升高，而其他中性氨基酸（除了 Met）的尿排泄量远高于其血清水平，表明 Cbs(-/-)（非 Cth(-/-)）小鼠存在中性氨基酸尿。由于大多数中性氨基酸通过 B(0)AT1 转运体吸收，并且 Met 对 B(0)AT1 的亲和力高于其他中性氨基酸，因此高蛋氨酸血症可能导致中性氨基酸的过度排泄。
