Background: Secondary hyperparathyroidism is characterized by parathyroid gland (PG) hyperplasia, and excessive synthesis and secretion of parathyroid hormone (PTH). Reduced vitamin D receptor (VDR) density has shown to play an essential role in PG hyperplasia progression; nevertheless, its exact mechanism remains unclear. VDR has shown to suppress the inflammation mediator NF-κB-mediated gene transcription. The aim of this study is to examine whether NF-κB is involved in the pathogenesis of parathyroid hyperplasia.
Methods: 35 PGs was obtained from 10 maintenance hemodialysis patients who underwent parathyroidectomy surgery. 5/6-nephrectomized rats fed with a high-phosphate diet were divided into four groups: (1) Nx + vehicle group, treated with vehicle; (2) Nx + PDTC prevention group, treated with NF-κB inhibitor PDTC for 2 months; (3) Nx + PDTC therapy group, treated with PDTC for 1 month; (4) Nx + calcitriol group, treated with activated vitamin D calcitriol for 1 month. Ten sham-operated rats fed with normal-phosphate diet were used as a control group. Serum calcium, phosphorus, creatinine, Blood urea nitrogen (BUN), intact PTH and PG size in rats were measured. Proliferating cell nuclear antigen (PCNA), VDR, NF-κB of PGs were examined using immunohistochemistry and western blot.
Results: The activation of NF-κB pathway in the nodular hyperplasia gland was significantly increased compared with the diffuse hyperplasia gland found in hemodialysis patients. Markedly higher serum creatinine, BUN, phosphorus levels, serum iPTH levels and larger PGs were found in Nx rats fed with a high-phosphate diet compared to sham-operated rats. Also, PCNA levels and activation of NF-κB pathway in PGs were higher compared with the sham group, meanwhile the VDR levels decreased. Contrary, treating rats with PDTC and calcitriol notably reduced serum iPTH, expression of PCNA and activation of NF-κB pathway, and decreased the enlargement of PGs in those animals.
Conclusions: NF-κB plays an important role in PG hyperplasia progression. VDR deficiency may be involved in the parathyroid gland hyperplasia through the activation of NF-κB pathway.
Keywords: End-stage renal disease; Hyperparathyroidism; NF-κB; Proliferation; Vitamin D receptor.