Parathyroid hormone (PTH) decreases sodium-phosphate cotransporter type IIa (NpT2a) mRNA stability.
Parathyroid hormone (PTH) decreases sodium-phosphate cotransporter type IIa (NpT2a) mRNA stability.
复制标题
甲状旁腺激素 (PTH) 会降低 IIa 型钠磷酸协同转运蛋白 (NpT2a) mRNA 的稳定性。
DOI：
10.1152/ajprenal.00632.2012
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
Lederer,EleanorD
中科院分区：
文献类型：
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作者：
Murray,RebeccaD;Holthouser,Kristine;Clark,BarbaraJ;Salyer,SarahA;Barati,MichelleT;Khundmiri,SyedJ;Lederer,EleanorD
甲状旁腺激素(PTH)对近曲小管Na~+-K~+-ATPase(Na~+-K~+-ATPase)和Na~(2+)依赖磷酸(NAPI)转运的急性抑制作用已被广泛研究，但对其慢性作用的研究较少。原发性甲状旁腺功能亢进症是一种以甲状旁腺激素慢性升高为特征的疾病，患者表现出持续性的低磷血症，但没有明显的盐耗迹象。我们推测，慢性甲状旁腺素刺激导致甲状旁腺素反应的不同脱敏。为了解决这一假设，我们比较了慢性甲状旁腺激素刺激对SD大鼠、甲状旁腺特异性细胞周期蛋白D1过度表达的转基因小鼠(PTH-D1)和近曲小管细胞培养模型中Na-PicoTransporter(Npt2a)表达和Na-K活性和表达的影响。甲状旁腺激素处理6h或4d后，Npt2a在刷状缘膜(BBM)的表达逐渐减少，而基底外侧膜(BLM)的Na-K表达和活性开始下降，4d后恢复到对照水平。与对照组相比，PTH-D1小鼠Npt2a蛋白表达降低，而Na-K、NHERF-1和PTH受体水平保持不变。在PTH-D1小鼠中，NpT2a mRNA的表达较对照小鼠降低50%。在负鼠肾脏近端小管细胞中，甲状旁腺素降低了Npt2a的mRNA水平。放线菌素D和放线菌亚胺处理均可阻止PTH介导的Npt2a基因表达下降，提示PTH反应需要转录和翻译。这些发现表明，对慢性甲状旁腺素暴露的反应是在转录后水平上选择性地调节的。对甲状旁腺素的持续的磷酸反应是通过转录后机制发生的。
The acute inhibitory effects of parathyroid hormone (PTH) on proximal tubule Na+-K+-ATPase (Na-K) and sodium-dependent phosphate (NaPi) transport have been extensively studied, while little is known about the chronic effects of PTH. Patients with primary hyperparathyroidism, a condition characterized by chronic elevations in PTH, exhibit persistent hypophosphatemia but not significant evidence of salt wasting. We postulate that chronic PTH stimulation results in differential desensitization of PTH responses. To address this hypothesis, we compared the effects of chronic PTH stimulation on Na-Picotransporter (Npt2a) expression and Na-K activity and expression in Sprague Dawley rats, transgenic mice featuring parathyroid-specific cyclin D1 overexpression (PTH-D1), and proximal tubule cell culture models. We demonstrated a progressive decrease in brush-border membrane (BBM) expression of Npt2a from rats treated with PTH for 6 h or 4 days, while Na-K expression and activity in the basolateral membranes (BLM) exhibited an initial decrease followed by recovery to control levels by 4 days. Npt2a protein expression in PTH-D1 mice was decreased relative to control animals, whereas levels of Na-K, NHERF-1, and PTH receptor remained unchanged. In PTH-D1 mice, NpT2a mRNA expression was reduced by 50% relative to control mice. In opossum kidney proximal tubule cells, PTH decreased Npt2a mRNA levels. Both actinomycin D and cycloheximide treatment prevented the PTH-mediated decrease in Npt2a mRNA, suggesting that the PTH response requires transcription and translation. These findings suggest that responses to chronic PTH exposure are selectively regulated at a posttranscriptional level. The persistence of the phosphaturic response to PTH occurs through posttranscriptional mechanisms.