Activator protein 2α mediates parathyroid TGF-α self-induction in secondary hyperparathyroidism

Maria Vittoria Arcidiacono, Mario Cozzolino, Noah Spiegel, Masanori Tokumoto, Jing Yang, Yan Lu, Tetsuhiko Sato, Carlo Lomonte, Carlo Basile, Eduardo Slatopolsky, Adriana S. Dusso

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

In secondary hyperparathyroidism, enhanced expression of TGF-α in the parathyroid leads to its own upregulation, generating a feed-forward loop for TGF-α activation of its receptor, EGFR receptor (EGFR), which promotes parathyroid hyperplasia. These studies examined the role of activator protein 2α(AP2), an inducer of TGF-α gene transcription, in the upregulation of parathyroid TGF-α in secondary hyperparathyroidism. In rat and human secondary hyperparathyroidism, parathyroid AP2 expression strongly correlated with TGF-α 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-α induced by high dietary phosphate. More significant, in A431 cells, which provide a model of enhanced TGF-α and TGF-α self-induction, mutating the core AP2 site of the human TGF-α promoter markedly impaired promoter activity induced by endogenous or exogenous TGF-α. Important for therapy, in five-sixths nephrectomized rats fed high-phosphate diets, inhibition of parathyroid TGF-α self-induction using erlotinib, a highly specific inhibitor of TGF-α/EGFR-driven signals, reduced AP2 expression dosage dependently. This suggests that the increases in parathyroid AP2 occur downstream of EGFR activation by TGF-α and are required for TGF-α self-induction. Indeed, in A431 cells, erlotinib inhibition of TGF-α self-induction caused parallel reductions in AP2 expression and nuclear localization, as well as TGF-α mRNA and protein levels. In summary, increased AP2 expression and transcriptional activity at the TGF-α promoter determine the severity of the hyperplasia driven by parathyroid TGF-α self-upregulation in secondary hyperparathyroidism.

Original languageEnglish
Pages (from-to)1919-1928
Number of pages10
JournalJournal of the American Society of Nephrology
Volume19
Issue number10
DOIs
StatePublished - Oct 2008

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