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Local NF-κB Activation Promotes Parathyroid Hormone Synthesis and Secretion in Uremic Patients.
- Source :
-
Endocrinology [Endocrinology] 2021 Jul 01; Vol. 162 (7). - Publication Year :
- 2021
-
Abstract
- Secondary hyperparathyroidism (SHPT) in uremic patients is characterized by parathyroid gland (PTG) hyperplasia and parathyroid hormone (PTH) elevation. Previously, we demonstrated that NF-κB activation contributed to parathyroid cell proliferation in rats with chronic kidney disease. Although vitamin D inhibits inflammation and ameliorates SHPT, the contribution of vitamin D deficiency to SHPT via local NF-κB activation remains to be clarified. PTGs collected from 10 uremic patients with advanced SHPT were used to test the expressions of vitamin D receptor (VDR), NF-κB, and proliferating cell nuclear antigen (PCNA). Freshly excised PTG tissues were incubated for 24 hours in vitro with VDR activator (VDRA) calcitriol or NF-κB inhibitor pyrrolidine thiocarbamate (PDTC). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to investigate the regulation of PTH transcription by NF-κB. We found higher levels of activated NF-κB and lower expression of VDR in nodular hyperplastic PTGs than in diffuse hyperplasia. In cultured PTG tissues, treatment with VDRA or PDTC inhibited NF-κB activation and PCNA expression, and downregulated preproPTH mRNA and intact PTH levels. ChIP assays demonstrated the presence of NF-κB binding sites in PTH promoter. Furthermore, in luciferase reporter assays, addition of exogenous p65 significantly increased PTH luciferase activity by 2.4-fold (P < 0.01), while mutation of NF-κB binding site at position -908 of the PTH promoter suppressed p65-induced PTH reporter activity (P < 0.01). In summary, local NF-κB activation contributes to SHPT and mediates the transcriptional activation of PTH directly in uremic patients. Vitamin D deficiency may be involved in SHPT via the activation of NF-κB pathway.<br /> (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Subjects :
- Calcitriol administration & dosage
Female
Humans
Hyperparathyroidism, Secondary drug therapy
Hyperparathyroidism, Secondary metabolism
Hyperparathyroidism, Secondary pathology
Hyperplasia
Male
Middle Aged
NF-kappa B antagonists & inhibitors
Parathyroid Glands chemistry
Parathyroid Glands pathology
Parathyroid Hormone biosynthesis
Parathyroid Hormone genetics
Proliferating Cell Nuclear Antigen analysis
Pyrrolidines administration & dosage
Receptors, Calcitriol analysis
Receptors, Calcitriol drug effects
Receptors, Calcitriol metabolism
Thiocarbamates administration & dosage
Tissue Culture Techniques
Transcription Factor RelA analysis
Transcription, Genetic drug effects
Uremia complications
Uremia pathology
NF-kappa B physiology
Parathyroid Glands metabolism
Parathyroid Hormone metabolism
Uremia metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7170
- Volume :
- 162
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 33912936
- Full Text :
- https://doi.org/10.1210/endocr/bqab084