Silva Ian V, Cebotaru Valeriu, Wang Hua, Wang Xi-Tao, Wang Sha Sha, Guo Gang, Devuyst Olivier, Thakker Rajesh V, Guggino William B, Guggino Sandra E
Department of Physiology, The Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
J Bone Miner Res. 2003 Apr;18(4):615-23. doi: 10.1359/jbmr.2003.18.4.615.
Dent's disease is a nephrolithiasis disorder associated with hypercalciuria and low molecular weight proteinuria that is caused by mutations in the voltage-gated chloride channel ClC-5. Because the exact cause of hypercalciuria in this disease is unknown and could come from a renal, intestinal, or bone origin, we have investigated overall calcium handling in the ClC-5 knockout mouse (ClC-5 KO). On a high calcium diet, ClC-5 KO mice had elevated serum 1alpha,25-dihydroxyvitamin D3 (1alpha,25D3), alkaline phosphatase (AP), osteocalcin (OC), and urinary deoxypyridinoline (DPD), but serum parathyroid hormone (PTH), calcium, and intestinal calcium uptake was similar to that of wild-type (WT) mice. A 30-fold decrease in dietary calcium intake caused elevation of serum PTH and urinary cyclic adenosine monophosphate in ClC-5 KO mice and decreased the renal calcium excretion, which still remained 2-fold above that of WT mice. On this low calcium diet, both groups of mice had the same serum 1alpha,25D3, with similar increments in intestinal calcium absorption, serum AP, OC, and urinary DPD. These data indicate that the hypercalciuria in the ClC-5 KO mice on low and high calcium diets is of bone and renal origin and is not caused by increased intestinal calcium absorption, despite an elevated serum 1alpha,25D3. These mice data suggest that young patients with this disease may have a propensity for altered bone homeostasis that should be monitored clinically.
丹特氏病是一种与高钙尿症和低分子量蛋白尿相关的肾结石疾病，由电压门控氯离子通道ClC-5的突变引起。由于该疾病中高钙尿症的确切病因尚不清楚，可能源于肾脏、肠道或骨骼，我们研究了ClC-5基因敲除小鼠（ClC-5 KO）的整体钙处理情况。在高钙饮食下，ClC-5 KO小鼠的血清1α,25-二羟基维生素D3（1α,25D3）、碱性磷酸酶（AP）、骨钙素（OC）和尿脱氧吡啶啉（DPD）升高，但血清甲状旁腺激素（PTH）、钙和肠道钙吸收与野生型（WT）小鼠相似。饮食钙摄入量减少30倍导致ClC-5 KO小鼠血清PTH和尿环磷酸腺苷升高，并降低了肾脏钙排泄，但其仍比WT小鼠高2倍。在这种低钙饮食下，两组小鼠的血清1α,25D3相同，肠道钙吸收、血清AP、OC和尿DPD的增加相似。这些数据表明，无论血清1α,25D3升高与否，低钙和高钙饮食下ClC-5 KO小鼠的高钙尿症源于骨骼和肾脏，而非肠道钙吸收增加。这些小鼠数据表明，患有这种疾病的年轻患者可能有骨稳态改变的倾向，应进行临床监测。
