Activator protein 2alpha mediates parathyroid TGF-alpha self-induction in secondary hyperparathyroidism.
J Am Soc Nephrol
; 19(10): 1919-28, 2008 Oct.
Article
en En
| MEDLINE
| ID: mdl-18579641
ABSTRACT
In secondary hyperparathyroidism, enhanced expression of TGF-alpha in the parathyroid leads to its own upregulation, generating a feed-forward loop for TGF-alpha activation of its receptor, EGFR receptor (EGFR), which promotes parathyroid hyperplasia. These studies examined the role of activator protein 2alpha (AP2), an inducer of TGF-alpha gene transcription, in the upregulation of parathyroid TGF-alpha in secondary hyperparathyroidism. In rat and human secondary hyperparathyroidism, parathyroid AP2 expression strongly correlated with TGF-alpha levels and with the rate of parathyroid growth, as expected. Furthermore, the increases in rat parathyroid content of AP2 and its binding to a consensus AP2 DNA sequence preceded the increase in TGF-alpha induced by high dietary phosphate. More significant, in A431 cells, which provide a model of enhanced TGF-alpha and TGF-alpha self-induction, mutating the core AP2 site of the human TGF-alpha promoter markedly impaired promoter activity induced by endogenous or exogenous TGF-alpha. Important for therapy, in five-sixths nephrectomized rats fed high-phosphate diets, inhibition of parathyroid TGF-alpha self-induction using erlotinib, a highly specific inhibitor of TGF-alpha/EGFR-driven signals, reduced AP2 expression dosage dependently. This suggests that the increases in parathyroid AP2 occur downstream of EGFR activation by TGF-alpha and are required for TGF-alpha self-induction. Indeed, in A431 cells, erlotinib inhibition of TGF-alpha self-induction caused parallel reductions in AP2 expression and nuclear localization, as well as TGF-alpha mRNA and protein levels. In summary, increased AP2 expression and transcriptional activity at the TGF-alpha promoter determine the severity of the hyperplasia driven by parathyroid TGF-alpha self-upregulation in secondary hyperparathyroidism.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Glándulas Paratiroides
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Uremia
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Factor de Crecimiento Transformador alfa
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Factor de Transcripción AP-2
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Hiperparatiroidismo Secundario
Tipo de estudio:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Am Soc Nephrol
Asunto de la revista:
NEFROLOGIA
Año:
2008
Tipo del documento:
Article
País de afiliación:
Estados Unidos