Molecular Mechanisms of Parathyroid Disorders in Chronic Kidney Disease

Abstract

Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that induces morbidity and mortality in patients. How CKD stimulates the parathyroid to increase parathyroid hormone (PTH) secretion, gene expression and cell proliferation remains an open question. In experimental SHP, the increased PTH gene expression is post-transcriptional and mediated by PTH mRNA-protein interactions that promote PTH mRNA stability. These interactions are orchestrated by the isomerase Pin1. Pin1 participates in conformational change-based regulation of target proteins, including mRNA-binding proteins. In SHP, Pin1 isomerase activity is decreased, and thus, the Pin1 target and PTH mRNA destabilizing protein KSRP fails to bind PTH mRNA, increasing PTH mRNA stability and levels. An additional level of post-transcriptional regulation is mediated by microRNA (miRNA). Mice with parathyroid-specific knockout of Dicer, which facilitates the final step in miRNA maturation, lack parathyroid miRNAs but have normal PTH and calcium levels. Surprisingly, these mice fail to increase serum PTH in response to hypocalcemia or uremia, indicating a role for miRNAs in parathyroid stimulation. SHP often leads to parathyroid hyperplasia. Reduced expressions of parathyroid regulating receptors, activation of transforming growth factor α-epidermal growth factor receptor, cyclooxygenase 2-prostaglandin E2 and mTOR signaling all contribute to the enhanced parathyroid cell proliferation. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. This review summarizes the current knowledge on the mechanisms that stimulate the parathyroid cell at multiple levels in SHP.

Keywords: microRNA; parathyroid cell proliferation; parathyroid hormone; post-transcriptional regulation; secondary hyperparathyroidism.

Figure 1

Model for the regulation of PTH mRNA stability in SHP by protein–PTH mRNA interactions and Pin1. Basal PTH mRNA levels are determined by a balanced interaction of the PTH mRNA 3′-UTR ARE with its stabilizing protein AUF1 and destabilizing protein KSRP that recruits the exosome (Pac-Man) to mRNAs. The isomerase Pin1 binds KSRP and induces KSRP Ser181 conformational change and dephosphorylation, which increases KSRP-PTH mRNA interaction and mRNA decay. In SHP, due to kidney failure or hypocalcemia, there is decreased parathyroid Pin1 isomerase activity and phosphorylated KSRP fails to bind PTH mRNA and recruit the exosome to it. As a result, AUF1 binds PTH mRNA with greater affinity, leading to increased PTH mRNA stability and levels. Schematic representation of the PTH mRNA with the coding sequence (CDS) in brown, the 5′- and 3′-untranslated regions (UTRs) in orange and ARE in red. AUF1, AU-rich binding factor 1; KSRP, K-homology splicing regulatory protein. Adapted with permission from the FASEB Journal [26].

Figure 2

Protein–mRNA interactions and miRNA determine the post-transcriptional increase in parathyroid hormone (PTH) gene expression in SHP. Decreased activity of the isomerase Pin1 in the parathyroid in SHP modifies protein–PTH mRNA interactions to increase PTH mRNA stability and levels in experimental chronic kidney failure. The stimulation of PTH expression is also dependent upon miRNA. Parathyroid miRNAs are dysregulated in both chronic kidney disease patients and experimental models. Mice with parathyroid specific knockout of Dicer, which prevents global miRNA maturation and function, fail to increase serum PTH after acute and chronic hypocalcemia or uremia, demonstrating that miRNAs are essential for parathyroid stimulation in SHP. Let-7 and miR-148 miRNA families that are dysregulated in CKD-SHP modify PTH secretion in vivo and in vitro, suggesting roles for these miRNAs in the increased PTH expression.

Figure 3

Regulators of PTH gene expression and parathyroid cell proliferation in SHP. Hyperphosphatemia and hypocalcemia stimulate and 1,25(OH)₂ vitamin D (1,25D) and fibroblast growth factor (FGF) 23 inhibit PTH production and parathyroid cell proliferation. In CKD-induced SHP, decreased expression of the CaSR, VDR and FGFR-klotho receptors together with activation of mTOR, TGF-α-EGFR and Cox-PGE2 signaling and changes in cell cycle regulators lead to hyperplastic parathyroid glands with high serum PTH levels. In the parathyroid cell, protein–PTH mRNA interactions mediated by activity of the isomerase Pin1 and miRNA increase PTH production and secretion. Adapted with permission from the International Journal of Molecular Sciences [99].