Gene and Stem Cell Therapy Programme, Centenary Institute, Missenden Road, Camperdown, New South Wales 2050, Australia.
Biochem J. 2010 May 27;428(3):397-407. doi: 10.1042/BJ20091667.
Renal maturation occurs post-natally in many species and reabsorption capacity at birth can vary substantially from the mature kidney. However, little is known regarding the maturation of amino acid transport mechanisms, despite the well-known physiological state of developmental iminoglycinuria. Commonly seen during early infancy, developmental iminoglycinuria is a transient version of the persistent inherited form of the disorder, referred to as iminoglycinuria, and manifests as a urinary hyperexcretion of proline, hydroxyproline and glycine. The transporters involved in developmental iminoglycinuria and their involvement in the improvement of renal reabsorption capacity remain unknown. qPCR (quantitative real-time PCR) and Western blot analysis in developing mouse kidney revealed that the expression of Slc6a18, Slc6a19, Slc6a20a and Slc36a2 was lower at birth (approx. 3.4-, 5.0-, 2.4- and 3.0-fold less than adult kidney by qPCR respectively) and increased during development. Furthermore, immunofluorescence confocal microscopy demonstrated the absence of apical expression of Slc6a18, Slc6a19, Slc6a20a and the auxiliary protein collectrin in kidneys of mice at birth. This correlated with the detection of iminoglycinuria during the first week of life. Iminoglycinuria subsided (proline reduction preceded glycine) in the second week of life, which correlated with an increase in the expression of Slc6a19 and Slc6a20a. Mice achieved an adult imino acid and glycine excretion profile by the fourth week, at which time the expression level of all transporters was comparable with adult mice. In conclusion, these results demonstrate the delayed expression and maturation of Slc6a18, Slc6a19, Slc6a20a and Slc36a2 in neonatal mice and thus the molecular mechanism of developmental iminoglycinuria.
在许多物种中，肾脏在出生后会继续发育，而出生时的肾脏重吸收能力与成熟肾脏有很大差异。然而，尽管发育性瓜氨酸尿症是一种众所周知的发育生理状态，但人们对氨基酸转运机制的成熟过程知之甚少。发育性瓜氨酸尿症在婴儿早期很常见，是该疾病持续性遗传形式的短暂版本，表现为脯氨酸、羟脯氨酸和甘氨酸的尿排泄过度。参与发育性瓜氨酸尿症的转运体及其在改善肾脏重吸收能力方面的作用尚不清楚。在发育中的小鼠肾脏中进行的 qPCR（定量实时 PCR）和 Western blot 分析显示，Slc6a18、Slc6a19、Slc6a20a 和 Slc36a2 的表达在出生时较低（通过 qPCR 分别比成年肾脏低约 3.4、5.0、2.4 和 3.0 倍），并在发育过程中增加。此外，免疫荧光共聚焦显微镜显示，出生时小鼠肾脏中 Slc6a18、Slc6a19、Slc6a20a 和辅助蛋白集钙蛋白的顶端表达缺失。这与生命第一周检测到瓜氨酸尿症的情况相关。生命的第二周，瓜氨酸尿症（脯氨酸减少先于甘氨酸）消退，这与 Slc6a19 和 Slc6a20a 的表达增加相关。小鼠在第四周时达到成年的氨基酸和甘氨酸排泄模式，此时所有转运体的表达水平与成年小鼠相当。总之，这些结果表明 Slc6a18、Slc6a19、Slc6a20a 和 Slc36a2 在新生小鼠中的表达和成熟延迟，这就是发育性瓜氨酸尿症的分子机制。
