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Am J Physiol Renal Physiol 289: F1096-F1102, 2005. First published July 5, 2005; doi:10.1152/ajprenal.00167.2005
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A critical role for enhanced TGF-{alpha} and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease

Mario Cozzolino,1,2 Yan Lu,1 Tetsuhiko Sato,1 Jing Yang,1 Ignacio Gonzalez Suarez,1 Diego Brancaccio,2 Eduardo Slatopolsky,1 and Adriana S. Dusso1

1Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and 2Renal Division, San Paolo Hospital, Milan, Italy

Submitted 20 April 2005 ; accepted in final form 29 June 2005

The parathyroid hyperplasia secondary to kidney disease is associated with enhanced expression of the growth promoter transforming growth factor-{alpha} (TGF-{alpha}). TGF-{alpha} stimulates growth through activation of its receptor, the epidermal growth factor receptor (EGFR), normally expressed in the parathyroid glands. Because enhanced coexpression of TGF-{alpha} and EGFR causes aggressive cellular growth, these studies utilized highly specific inhibitors of EGFR tyrosine kinase, a step mandatory for TGF-{alpha}-induced EGFR activation, to assess the contribution of growth signals from enhanced expression of TGF-{alpha} exclusively or both TGF-{alpha} and EGFR to the rapid parathyroid growth induced by kidney disease and exacerbated by high-phosphorus (P) and low-calcium (Ca) diets in rats. The enhancement in parathyroid gland weight and proliferating activity (proliferating cell nuclear antigen/Ki67) induced by kidney disease and aggravated by either high P or low Ca intake, within the first week after 5/6 nephrectomy, in rats, coincided with simultaneous increases (2- to 3-fold) in TGF-{alpha} and EGFR content. Conversely, prevention of the increases in both TGF-{alpha} and EGFR paralleled the efficacy of either P restriction or high-Ca intake in ameliorating uremia-induced parathyroid hyperplasia. More importantly, suppression of TGF-{alpha}/EGFR signaling, through prophylactic administration of potent and highly selective inhibitors of ligand-induced EGFR activation, completely prevented both high-P- and low-Ca-induced parathyroid hyperplasia as well as TGF-{alpha} self-upregulation. Thus enhanced parathyroid TGF-{alpha}/EGFR expression, self-upregulation, and growth signals occur early in kidney disease, are aggravated by low-Ca and high-P intake, and constitute the main pathogenic mechanism of the severity of parathyroid hyperplasia.

secondary hyperparathyroidism; growth arrest; epidermal growth factor receptor; tyrosine kinase inhibitor; renal failure


Address for reprint requests and other correspondence: A. Dusso, Renal Div., Box 8126, Dept. of Internal Medicine, 660 S. Euclid Ave., St. Louis, MO 63110 (e-mail: adusso{at}im.wustl.edu)




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