The parathyroid hyperplasia secondary to kidney disease is associated with enhanced expression of the growth promoter transforming growth factor- (TGF-). TGF- stimulates growth through activation of its receptor, the epidermal growth factor receptor (EGFR), normally expressed in the parathyroid glands. Because enhanced coexpression of TGF- and EGFR causes aggressive cellular growth, these studies utilized highly specific inhibitors of EGFR tyrosine kinase, a step mandatory for TGF--induced EGFR activation, to assess the contribution of growth signals from enhanced expression of TGF- exclusively or both TGF- 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- and EGFR content. Conversely, prevention of the increases in both TGF- and EGFR paralleled the efficacy of either P restriction or high-Ca intake in ameliorating uremia-induced parathyroid hyperplasia. More importantly, suppression of TGF-/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- self-upregulation. Thus enhanced parathyroid TGF-/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.
|Titolo:||A critical role for enhanced TGF-alpha and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease|
COZZOLINO, MARIO GENNARO (Primo)
|Parole Chiave:||Epidermal growth factor receptor; Growth arrest; Renal failure; Secondary hyperparathyroidism; Tyrosine kinase inhibitor|
|Data di pubblicazione:||nov-2005|
|Digital Object Identifier (DOI):||10.1152/ajprenal.00167.2005|
|Appare nelle tipologie:||01 - Articolo su periodico|