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Increased Parathyroid Hormone Gene Expression in Secondary Hyperparathyroidism of Experimental Uremia Is Reversed by Calcimimetics: Correlation with Posttranslational Modification of the Trans Acting Factor AUF1

Ronen Levi^*, Iddo Z. Ben-Dov^*, Vardit Lavi-Moshayoff^*, Maya Dinur^*, David Martin, Tally Naveh-Many^* and Justin Silver^*

^* Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hebrew University Hadassah Medical Center, Jerusalem, Israel; and Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, California

Address correspondence to: Dr. Justin Silver, Nephrology Services, Hadassah Hospital, P.O. Box 12000, Jerusalem, Israel 91120. Phone: +972-2-6436778; Fax: +972-2-6421234; E-mail:silver{at}huji.ac.il

Received for publication July 5, 2005. Accepted for publication September 28, 2005.

Most patients with chronic kidney disease develop secondary hyperparathyroidism with disabling systemic complications. Calcimimetic agents are effective tools in the management of secondary hyperparathyroidism, acting through allosteric modification of the calcium-sensing receptor (CaR) on the parathyroid gland (PT) to decrease parathyroid hormone (PTH) secretion and PT cell proliferation. This study showed that rats that were fed an adenine high-phosphorus diet had increased serum PTH and PTH mRNA levels at 7 and 21 d. For studying the effect of activation of the CaR by the calcimimetics R-568 on PTH gene expression, R-568 was given by gavage to uremic rats for the last 4 d of a 7-d adenine high-phosphorus diet. R-568 decreased both PTH mRNA and serum PTH levels. The effect of the calcimimetic on PTH gene expression was posttranscriptional and correlated with differences in protein–RNA binding and posttranslational modifications of the trans acting factor AUF1 in the PT. The AUF1 modifications as a result of uremia were reversed by treatment with R-568 to those of normal rats. Therefore, uremia and activation of the CaR mediated by calcimimetics modify AUF1 posttranslationally. These modifications in AUF1 correlate with changes in protein–PTH mRNA binding and PTH mRNA levels.

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