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Activator Protein 2 Mediates Parathyroid TGF- 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^* and Adriana S. Dusso^*

^* Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and Miulli Hospital, Acquaviva delle fonti, Bari, Italy

Correspondence: Dr. Adriana Dusso, Renal Division, Box 8126, Department of Internal Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110. Phone: 314-362-8248; Fax: 314-362-8237; E-mail: adusso{at}im.wustl.edu

Received for publication November 18, 2007. Accepted for publication April 26, 2008.

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

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673