The induction of C/EBPβ contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease.
Data de publicació2015-03-01
MetadadesMostra el registre d'unitat complet
Abstract BACKGROUND: In secondary hyperparathyroidism (SHPT), enhanced parathyroid levels of transforming growth factor-α (TGFα) increase EGF receptor (EGFR) activation causing parathyroid hyperplasia, high parathyroid hormone (PTH) and also reductions in vitamin D receptor (VDR) that limit vitamin D suppression of SHPT. Since anti-EGFR therapy is not an option in human SHPT, we evaluated ADAM17 as a therapeutic target to suppress parathyroid hyperplasia because ADAM17 is required to release mature TGFα, the most potent EGFR-activating ligand. METHODS: Computer analysis of the ADAM17 promoter identified TGFα and C/EBPβ as potential regulators of the ADAM17 gene. Their regulation of ADAM17 expression, TGFα/EGFR-driven growth and parathyroid gland (PTG) enlargement were assessed in promoter-reporter assays in A431 cells and corroborated in rat and human SHPT, using erlotinib as anti-EGFR therapy to suppress TGFα signals, active vitamin D to induce C/EBPβ or the combination. RESULTS: While TGFα induced ADAM17-promoter activity by 2.2-fold exacerbating TGFα/EGFR-driven growth, ectopic C/EBPβ expression completely prevented this vicious synergy. Accordingly, in advanced human SHPT, parathyroid ADAM17 levels correlated directly with TGFα and inversely with C/EBPβ. Furthermore, combined erlotinib + calcitriol treatment suppressed TGFα/EGFR-cell growth and PTG enlargement more potently than erlotinib in part through calcitriol induction of C/EBPβ to inhibit ADAM17-promoter activity, mRNA and protein. Importantly, in rat SHPT, the correction of vitamin D deficiency effectively reversed the resistance to paricalcitol induction of C/EBPβ to suppress ADAM17 expression and PTG enlargement, reducing PTH by 50%. CONCLUSION: In SHPT, correction of vitamin D and calcitriol deficiency induces parathyroid C/EBPβ to efficaciously attenuate the severe ADAM17/TGFα synergy, which drives PTG enlargement and high PTH.
És part deNephrology Dialysis Transplantation, 2015, vol. 30, num. 3, p. 423-433
Projectes de recerca europeus
Mostrant elements relacionats per títol, autor i matèria.
A low fractional excretion of Phosphate/Fgf23 ratio is associated with severe abdominal Aortic calcification in stage 3 and 4 kidney disease patients Craver Hospital, Lourdes; Dusso Rosso, Adriana; Martínez Alonso, Montserrat; Sarró, Felipe; Valdivielso Revilla, José Manuel; Fernández i Giráldez, Elvira (BioMed Central, 2013)Background: Vascular calcification (VC) contributes to high mortality rates in chronic kidney disease (CKD). High serum phosphate and FGF23 levels and impaired phosphaturic response to FGF23 may affect VC. Therefore, ...
A Novel Rat Model of Vitamin D Deficiency: Safe and Rapid Induction of Vitamin D and Calcitriol Deficiency without Hyperparathyroidism Stavenuiter, Andrea W. D.; Arcidiacono, Maria V.; Ferrantelli, Evelina; Keuning, Eelco D.; Vila Cuenca, Marc; Wee, Piet M. ter; Beelen, Robert H. J.; Vervloet, Marc G.; Dusso Rosso, Adriana (Hindawi, 2015)Vitamin D deficiency is associated with a range of clinical disorders. To study the mechanisms involved and improve treatments, animal models are tremendously useful. Current vitamin D deficient rat models have important ...
Vascular calcification induced by chronic kidney disease is mediated by an increase of 1α-hydroxylase expression in vascular smooth muscle cells Torremadé Pascual, Noèlia; Bozić Stanojević, Milica; Panizo García, Sara; Barrio Vazquez, Sara; Fernandez Martín, José L.; Encinas Martín, Mario; Goltzman, David; Arcidiacono, Maria V.; Fernández i Giráldez, Elvira; Valdivielso Revilla, José Manuel (Wiley, 2016-04-01)Vascular calcification (VC) is a complication of chronic kidney disease that predicts morbidity and mortality. Uremic serum promotes VC, but the mechanism involved is unknown. A role for 1,25(OH)2 D3 in VC has been proposed, ...