HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

A critical role for enhanced TGF-alpha and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease.

Abstract
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.
AuthorsMario Cozzolino, Yan Lu, Tetsuhiko Sato, Jing Yang, Ignacio Gonzalez Suarez, Diego Brancaccio, Eduardo Slatopolsky, Adriana S Dusso
JournalAmerican journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 289 Issue 5 Pg. F1096-102 (Nov 2005) ISSN: 1931-857X [Print] United States
PMID15998841 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Calcium, Dietary
  • Phosphorus, Dietary
  • Transforming Growth Factor alpha
  • ErbB Receptors
Topics
  • Animals
  • Calcium, Dietary (metabolism)
  • ErbB Receptors (biosynthesis, physiology)
  • Female
  • Hyperplasia
  • Kidney Diseases (complications, veterinary)
  • Parathyroid Glands (pathology)
  • Phosphorus, Dietary (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Severity of Illness Index
  • Transforming Growth Factor alpha (biosynthesis, physiology)
  • Up-Regulation

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: