The induction of C/EBPβ contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease.
The induction of C/EBPβ contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease.
复制标题
C/EBPβ 的诱导有助于维生素 D 抑制 ADAM17 表达和肾脏疾病中的甲状旁腺增生。
DOI：
10.1093/ndt/gfu311
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Dusso,Adriana
中科院分区：
文献类型：
--
作者：
Arcidiacono,MariaVittoria;Yang,Jing;Fernandez,Elvira;Dusso,Adriana
背景在继发性甲状旁腺功能亢进（SHPT）中，甲状旁腺中转化生长因子-α（TGFα）水平升高，表皮生长因子受体（EGFR）激活增加，导致甲状旁腺增生，甲状旁腺激素（PTH）升高，维生素D受体（VDR）减少，限制维生素D抑制SHPT。由于抗EGFR治疗不是一种选择，在人类SHPT，我们评估了ADAM 17作为一个治疗目标，以抑制甲状旁腺增生，因为ADAM 17是释放成熟的TGFα，最有效的EGFR激活ligand.MethodsComputer分析的ADAM 17启动子确定TGFα和C/EBPβ作为潜在的调节因子的ADAM 17基因。在A431细胞中的启动子-报告基因测定中评估了它们对ADAM 17表达、TGFα/EGFR驱动的生长和甲状旁腺（PTG）增大的调节，并在大鼠和人SHPT中得到证实，使用厄洛替尼作为抗EGFR治疗来抑制TGFα信号，使用活性维生素D来诱导C/EBPβ或组合。异位C/EBPβ表达完全阻止了这种恶性协同作用。因此，在晚期SHPT中，甲状旁腺ADAM 17水平与TGFα直接相关，与C/EBPβ呈负相关。此外，厄洛替尼+骨化三醇联合治疗抑制TGFα/EGFR-细胞生长和PTG增大的作用比厄洛替尼更强，部分原因是骨化三醇诱导C/EBPβ抑制ADAM 17启动子活性、mRNA和蛋白。重要的是，在大鼠SHPT中，维生素D缺乏的纠正有效逆转了对帕立骨化醇诱导的C/EBPβ的抵抗，从而抑制了ADAM 17表达和PTG增大，使PTH降低了50%.Conclusion在SHPT中，维生素D和骨化三醇缺乏的纠正诱导甲状旁腺C/EBPβ有效减弱了严重的ADAM 17/TGFα协同作用，从而驱动PTG增大和高PTH。
BackgroundIn secondary hyperparathyroidism (SHPT), enhanced parathyroid levels of transforming growth factor-α (TGFα) increase EGF receptor (EGFR) activation causing parathyroid hyperplasia, high parathyroid hormone (PTH) and also reductions in vitamin D receptor (VDR) that limit vitamin D suppression of SHPT. Since anti-EGFR therapy is not an option in human SHPT, we evaluated ADAM17 as a therapeutic target to suppress parathyroid hyperplasia because ADAM17 is required to release mature TGFα, the most potent EGFR-activating ligand.MethodsComputer analysis of the ADAM17 promoter identified TGFα and C/EBPβ as potential regulators of the ADAM17 gene. Their regulation of ADAM17 expression, TGFα/EGFR-driven growth and parathyroid gland (PTG) enlargement were assessed in promoter–reporter assays in A431 cells and corroborated in rat and human SHPT, using erlotinib as anti-EGFR therapy to suppress TGFα signals, active vitamin D to induce C/EBPβ or the combination.ResultsWhile TGFα induced ADAM17-promoter activity by 2.2-fold exacerbating TGFα/EGFR-driven growth, ectopic C/EBPβ expression completely prevented this vicious synergy. Accordingly, in advanced human SHPT, parathyroid ADAM17 levels correlated directly with TGFα and inversely with C/EBPβ. Furthermore, combined erlotinib + calcitriol treatment suppressed TGFα/EGFR-cell growth and PTG enlargement more potently than erlotinib in part through calcitriol induction of C/EBPβ to inhibit ADAM17-promoter activity, mRNA and protein. Importantly, in rat SHPT, the correction of vitamin D deficiency effectively reversed the resistance to paricalcitol induction of C/EBPβ to suppress ADAM17 expression and PTG enlargement, reducing PTH by 50%.ConclusionIn SHPT, correction of vitamin D and calcitriol deficiency induces parathyroid C/EBPβ to efficaciously attenuate the severe ADAM17/TGFα synergy, which drives PTG enlargement and high PTH.