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Kidney Failure Alters Parathyroid Pin1 Phosphorylation and Parathyroid Hormone mRNA-Binding Proteins, Leading to Secondary Hyperparathyroidism
Journal of the American Society of Nephrology ( IF 13.6 ) Pub Date : 2022-09-01 , DOI: 10.1681/asn.2022020197
Alia Hassan 1 , Yael E Pollak 1 , Rachel Kilav-Levin 1, 2 , Justin Silver 1 , Nir London 3 , Morris Nechama 4, 5 , Iddo Z Ben-Dov 6 , Tally Naveh-Many 1, 5
Affiliation  

Background

Secondary hyperparathyroidism (SHP) is a common complication of CKD that increases morbidity and mortality. In experimental SHP, increased parathyroid hormone (PTH) expression is due to enhanced PTH mRNA stability, mediated by changes in its interaction with stabilizing AUF1 and destabilizing KSRP. The isomerase Pin1 leads to KSRP dephosphorylation, but in SHP parathyroid Pin1 activity is decreased and hence phosphorylated KSRP fails to bind PTH mRNA, resulting in high PTH mRNA stability and levels. The up- and downstream mechanisms by which CKD stimulates the parathyroid glands remain elusive.

Methods

Adenine-rich high-phosphate diets induced CKD in rats and mice. Parathyroid organ cultures and transfected cells were incubated with Pin1 inhibitors for their effect on PTH expression. Mass spectrometry was performed on both parathyroid and PTH mRNA pulled-down proteins.

Results

CKD led to changes in rat parathyroid proteome and phosphoproteome profiles, including KSRP phosphorylation at Pin1 target sites. Furthermore, both acute and chronic kidney failure led to parathyroid-specific Pin1 Ser16 and Ser71 phosphorylation, which disrupts Pin1 activity. Pharmacologic Pin1 inhibition, which mimics the decreased Pin1 activity in SHP, increased PTH expression ex vivo in parathyroid glands in culture and in transfected cells through the PTH mRNA-protein interaction element and KSRP phosphorylation.

Conclusions

Kidney failure leads to loss of parathyroid Pin1 activity by inducing Pin1 phosphorylation. This predisposes parathyroids to increase PTH production through impaired PTH mRNA decay that is dependent on KSRP phosphorylation at Pin1-target motifs. Pin1 and KSRP phosphorylation and the Pin1-KSRP-PTH mRNA axis thus drive SHP.



中文翻译:

肾衰竭改变甲状旁腺 Pin1 磷酸化和甲状旁腺激素 mRNA 结合蛋白,导致继发性甲状旁腺功能亢进

背景

继发性甲状旁腺功能亢进症 (SHP) 是 CKD 的常见并发症,会增加发病率和死亡率。在实验性 SHP 中,甲状旁腺激素 (PTH) 表达增加是由于PTH mRNA 稳定性增强,这是由其与稳定 AUF1 和不稳定 KSRP 相互作用的变化介导的。异构酶 Pin1 导致 KSRP 去磷酸化,但在 SHP 中,甲状旁腺 Pin1 活性降低,因此磷酸化的 KSRP 无法结合PTH mRNA,导致PTH mRNA 稳定性和水平较高。CKD 刺激甲状旁腺的上下游机制仍然难以捉摸。

方法

富含腺嘌呤的高磷酸盐饮食可诱发大鼠和小鼠的 CKD。将甲状旁腺器官培养物和转染细胞与 Pin1 抑制剂一起孵育,以观察其对 PTH 表达的影响。对甲状旁腺和PTH mRNA 下拉蛋白进行质谱分析。

结果

CKD 导致大鼠甲状旁腺蛋白质组和磷酸化蛋白质组谱发生变化,包括 Pin1 靶位点的 KSRP 磷酸化。此外,急性和慢性肾衰竭都会导致甲状旁腺特异性 Pin1 Ser16 和 Ser71 磷酸化,从而破坏 Pin1 活性。药理学 Pin1 抑制模拟 SHP 中 Pin1 活性的降低,通过PTH mRNA-蛋白质相互作用元件和 KSRP 磷酸化,体外培养的甲状旁腺和转染细胞中增加 PTH 表达。

结论

肾衰竭通过诱导 Pin1 磷酸化导致甲状旁腺 Pin1 活性丧失。这使得甲状旁腺倾向于通过受损的PTH mRNA 衰减来增加 PTH 的产生,而 PTH mRNA 的衰减依赖于 Pin1 靶基序上的 KSRP 磷酸化。Pin1 和 KSRP 磷酸化以及 Pin1-KSRP- PTH mRNA 轴因此驱动 SHP。

更新日期:2022-09-01
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