Foreman J W, Benson L L, Wellons M, Avner E D, Sweeney W, Nissim I, Nissim I
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
J Am Soc Nephrol. 1995 Aug;6(2):269-72. doi: 10.1681/ASN.V62269.
The cause of Fanconi syndrome in cystinosis is enigmatic. It has previously been shown that renal tubules could be loaded with cystine by incubating them with cystine dimethylester (CDE), mimicking the biochemical hallmark of cystinosis. Such tubules have impaired transport, decreased whole-cell O2 consumption, and substrate utilization. In this study, the metabolic disturbances in cystine-loaded renal tubule cells were further characterized. Isolated rat renal tubules were loaded with cystine by incubating them with 2 mM CDE for 10 min. This had no significant effect on total ATPase, Na(+)-K(+)-ATPase, or the ouabain-insensitive ATPase activity of renal tissue homogenates from these cystine-loaded tubules. Intracellular K was significantly lower in the cystine-loaded tubules (37 +/- 2 versus 47 +/- 3 nEq/mg; P < 0.008). Intracellular ATP was reduced by 39% in the cystine-loaded tubules (23.7 +/- 2.4 versus 38.1 +/- 3.3 nmol/mg of protein; P < 0.0025). CDE (2 mM) reduced isolated mitochondrial O2 consumption with glutamate as the substrate by 66% (4.7 +/- 0.7 versus 13.9 +/- 0.8 nm/min per mg of protein, P < 0.001) but had no effect on mitochondrial O2 consumption with succinate as the substrate. It was speculated that the impaired transport from cystine loading with CDE is secondary to a decrease in energy generation.
胱氨酸病中范科尼综合征的病因尚不明确。此前的研究表明，通过将肾小管与胱氨酸二甲酯（CDE）孵育，可使肾小管中充满胱氨酸，这模拟了胱氨酸病的生化特征。这样的肾小管运输功能受损，全细胞耗氧量及底物利用率降低。在本研究中，对胱氨酸负荷的肾小管细胞中的代谢紊乱进行了进一步的特征描述。将分离的大鼠肾小管与2 mM CDE孵育10分钟，使其充满胱氨酸。这对这些胱氨酸负荷的肾小管的肾组织匀浆中的总ATP酶、钠钾ATP酶或哇巴因不敏感ATP酶活性没有显著影响。胱氨酸负荷的肾小管中的细胞内钾显著降低（37±2对47±3 nEq/mg；P<0.008）。胱氨酸负荷的肾小管中的细胞内ATP减少了39%（23.7±2.4对38.1±3.3 nmol/mg蛋白质；P<0.0025）。2 mM的CDE使以谷氨酸为底物的分离线粒体耗氧量降低了66%（4.7±0.7对13.9±0.8 nm/min per mg蛋白质，P<0.001），但对以琥珀酸为底物的线粒体耗氧量没有影响。据推测，CDE导致的胱氨酸负荷引起的运输功能受损继发于能量生成的减少。
