Mechanism of calcitriol regulating parathyroid cells in secondary hyperparathyroidism

Abstract

A common consequence of chronic renal disease is secondary hyperparathyroidism (SHPT) and is closely related to the mortality and morbidity of uremia patients. Secondary hyperparathyroidism (SHPT) is caused by excessive PTH production and release, as well as parathyroid enlargement. At present, the mechanism of cell proliferation in secondary hyperparathyroidism (SHPT) is not completely clear. Decreased expression of the vitamin D receptor (VDR) and calcium-sensing receptor (CaSR), and 1,25(OH)2D3 insufficiency all lead to a decrease in cell proliferation suppression, and activation of multiple pathways is also involved in cell proliferation in renal hyperparathyroidism. The interaction between the parathormone (PTH) and parathyroid hyperplasia and 1,25(OH)2D3 has received considerable attention. 1,25(OH)2D3 is commonly applied in the therapy of renal hyperparathyroidism. It regulates the production of parathormone (PTH) and parathyroid cell proliferation through transcription and post-transcription mechanisms. This article reviews the role of 1,25(OH)2D3 in parathyroid cells in secondary hyperparathyroidism and its current understanding and potential molecular mechanism.

Keywords: calcitriol; chronic kidney disease; parathyroid cells; regulatory mechanisms; secondary hyperparathyroidism.

FIGURE 1

Mechanism of calcitriol in parathyroid cells. In the cell, 1,25D binds to VDR, which is translocated to the nucleus.1, 25D-bound VDR can form different complexes in different promoter regions. By binding to RXR and VDIR, it recruits histone deacetylases HDAC2 and DNA methyltransferases DNMT1 and DNMT3b to inhibit transcription of the PTH gene, thereby reducing the synthesis and secretion of PTH. 1, 25D-bound VDR induces transcription of calcium-sensing receptor (CaSR), Klotho, VDR, Let-7, c-myc, CDKN1a and CDKN1b genes by directly binding RXR to vitamin D response elements on DNA. Increased CaSR expression leads to higher sensitivity of parathyroid cells to calcium, while increased Klotho transcription results in increased sensitivity to FGF23. c-myc, p21 and p27 supress cell proliferation by inhibiting cell cycle progression. The increased transcription of Let-7 family decreased the stability of PTH mRNA. 1,25D also represses the proliferation of Parathyroid cells by reducing epidermal growth factor receptor (EGFR), Nuclear factor-KB (NF-kB), mTOR complex 1(mTORc1) and prostaglandin E2(PGE2) signaling pathways.