Dabbagh S, Gusowski N, Padilla M, Theissen M, Chesney R W
Department of Pediatrics, University of Wisconsin Clinical Science Center.
Biochem Med Metab Biol. 1990 Aug;44(1):64-76. doi: 10.1016/0885-4505(90)90046-4.
Vitamin D deficiency is characterized by secondary hyperparathyroidism, phosphaturia, bicarbonaturia, and generalized amino aciduria. While the site at which the phosphaturia ensues has been described to occur at the apical membrane of the renal proximal tubule, no studies are available for amino aciduria. Thus, weanling rats were fed five vitamin D-deficient diets for 4-6 weeks: (i) VLC, 0.02% Ca, 0.3% P; (ii) VLC + 1,25[OH]2D, same + 500 pmole ip for 2 days; (iii) LC, 0.45% Ca, 0.3% P; (iv) HC, 2.5% Ca, 0.3% P; and (v) VLP, 1.2% cA, 0.1% P. The normal diet contained 1.2% Ca, 0.7% P, and 2.5 micrograms% vitamin D. Amino acids, serum 25[OH]D, 1,25[OH]2D, and PTH, using a specific anti-rat PTH antibody, were measured. There were 4.65 +/- 1.1- and 10 +/- 1.39-fold increases in the urinary excretion of taurine and proline, respectively, irrespective of diet. Hypocalcemia, secondary hyperparathyroidism, and increased concentrations of urinary cAMP were demonstrated in all diets, except VLP. Taurinuria and prolinuria manifested at the renal brush border membrane. There was 21-25% and 26-39% attenuation in the peak of the overshoot of Na(+)-dependent uptake of taurine and proline, respectively, that was statistically significant as compared to that of normal diets (P less than 0.01). VLC resulted in a reduction in the Vmax of taurine (VLC, 78.26 +/- 6.88 vs normal, 115.4 +/- 6.26 pmole/mg protein/min, P less than 0.01) and proline (VLC, 402.06 +/- 31.26 vs normal, 589.49 +/- 37.42 pmole/mg protein/15 sec, P less than 0.01) uptake. Acute supplementation with pharmacological doses of 1,25[OH]2D normalized the Vmax of taurine and proline uptake, without affecting their renal excretion. The VLP diet induced and increase in the Km of taurine (VLP, 58.95 +/- 1.88 microM vs normal, 39.75 +/- 2.75 microM P less than 0.01) and proline (VLP, 116.75 +/- 8.87 microM vs normal, 76.82 +/- 7.27 microM P less than 0.01) uptake, without an associated perturbation in the Vmax of uptake. We conclude that the amino aciduria of vitamin D deficiency manifests at the apical membrane of the proximal tubule by an attenuation in the Na(+)-dependent uptake of amino acids. This is associated with a reduction in the initial rate of uptake or number of active transporters in the presence of secondary hyperparathyroidism and hypocalcemia, or a decrease in the affinity of the symport in the presence of P depletion. The data suggest the interplay of multiple factors in the causation of amino aciduria.
维生素D缺乏的特征为继发性甲状旁腺功能亢进、磷酸盐尿、重碳酸盐尿和全身性氨基酸尿。虽然磷酸盐尿的发生部位已被描述为在肾近端小管的顶端膜，但关于氨基酸尿的研究尚无。因此，给断奶大鼠喂食五种维生素D缺乏饮食4 - 6周：(i)极低钙（VLC），0.02%钙，0.3%磷；(ii)VLC + 1,25[OH]₂D，相同饮食加500皮摩尔腹腔注射，共2天；(iii)低钙（LC），0.45%钙，0.3%磷；(iv)高钙（HC），2.5%钙，0.3%磷；以及(v)极低磷（VLP），1.2%钙，0.1%磷。正常饮食含1.2%钙，0.7%磷和2.5微克%维生素D。使用特异性抗大鼠甲状旁腺激素（PTH）抗体测定氨基酸、血清25[OH]D、1,25[OH]₂D和PTH。无论饮食如何，牛磺酸和脯氨酸的尿排泄量分别增加了4.65±1.1倍和10±1.39倍。除VLP饮食外，所有饮食均出现低钙血症、继发性甲状旁腺功能亢进和尿cAMP浓度升高。牛磺酸尿症和脯氨酸尿症出现在肾刷状缘膜。与正常饮食相比，牛磺酸和脯氨酸的钠依赖性摄取峰值分别衰减了21 - 25%和26 - 39%，具有统计学意义（P < 0.01）。VLC导致牛磺酸（VLC，78.26±6.88对正常，115.4±6.26皮摩尔/毫克蛋白/分钟，P < 0.01）和脯氨酸（VLC，402.06±31.26对正常，589.49±37.42皮摩尔/毫克蛋白/15秒，P < 0.01）摄取的Vmax降低。急性补充药理剂量的1,25[OH]₂D可使牛磺酸和脯氨酸摄取的Vmax恢复正常，而不影响其肾排泄。VLP饮食导致牛磺酸（VLP，58.95±1.88微摩尔对正常，39.75±2.75微摩尔，P < 0.01）和脯氨酸（VLP，116.75±8.87微摩尔对正常，76.82±7.27微摩尔，P < 0.01）摄取的Km增加，而摄取的Vmax无相关扰动。我们得出结论，维生素D缺乏导致的氨基酸尿通过近端小管顶端膜对氨基酸的钠依赖性摄取衰减而表现出来。这与继发性甲状旁腺功能亢进和低钙血症时摄取的初始速率降低或活性转运体数量减少有关，或者与磷缺乏时同向转运体的亲和力降低有关。数据表明多种因素在氨基酸尿的病因中相互作用。
