Elevated parathyroid hormone (PTH) levels cause osteitis fibrosa, bone loss and cardiovascular complications, all of which contribute significantly to increased morbidity and mortality in renal failure. Hyperplasia of PTH-producing cells is a major cause of high serum PTH levels. While it is known that hypocalcemia, hyperphosphatemia, and vitamin D deficiency promote parathyroid (PT) hyperplasia in renal failure, the underlying mechanisms are poorly understood. Our studies of PT growth in uremic rats fed a high P diet have shown that activation of the TGFa/EGFR pathway is a major contributor to PT hyperplasia. Inhibition of EGFR activation by AG1478, a highly specific EGFR-tyrosine kinase inhibitor (TKI), reduces uremia- and high P-induced PT hyperplasia by 60%. This finding raises the hypothesis that the potent inhibition of PT hyperplasia by vitamin D could result from downregulation of TGFa/EGFR growth signals. In fact, vitamin D suppresses the PT cell growth induced by uremia and high P by preventing increases in TGFa and EGFR. In vitro, vitamin D arrests the growth driven by EGFR overexpression by antagonizing EGFR-activation of ERKI/2 and transactivation of cyclin D1, and potentiates the growth arrest induced by maximally inhibitory doses of AG1478. The latter demonstrates antiproliferative vitamin D actions that are EGFR-independent. The overall goal of this proposal is to characterize the antagonistic interactions between vitamin D and TGFa/EGFR and their relevance in the pathogenesis and treatment of parathyroid hyperplasia. To this end, we propose to use TKI, 1,25D and combined therapy to identify: 1) Actual contribution of activation of the autocrine TGFa/EGFR-growth loop to parathyroid hyperplasia and vitamin D resistance in early and advanced renal failure. 2) EGFR-dependent and independent mechanisms mediating vitamin D-suppression of parathyroid hyperplasia. 3) Molecular mechanisms mediating vitamin D-inhibition of EGFR-growth signals in EGFR overexpressing cells. 4) Mechanisms mediating vitamin D-potentiation of TKI-inhibition of growth in EGFR overexpressing cells. By identifying pathogenic mechanisms, these studies should help design more effective therapies for secondary hyperparathyroidism. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062713-04
Application #
7072659
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Malozowski, Saul N
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$207,298
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Dusso, Adriana S; Tokumoto, Masanori (2011) Defective renal maintenance of the vitamin D endocrine system impairs vitamin D renoprotection: a downward spiral in kidney disease. Kidney Int 79:715-29
Dusso, Adriana; Arcidiacono, Maria Vittoria; Yang, Jing et al. (2010) Vitamin D inhibition of TACE and prevention of renal osteodystrophy and cardiovascular mortality. J Steroid Biochem Mol Biol 121:193-8
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Arcidiacono, Maria Vittoria; Cozzolino, Mario; Spiegel, Noah et al. (2008) Activator protein 2alpha mediates parathyroid TGF-alpha self-induction in secondary hyperparathyroidism. J Am Soc Nephrol 19:1919-28
Dusso, A S; Sato, T; Arcidiacono, M V et al. (2006) Pathogenic mechanisms for parathyroid hyperplasia. Kidney Int Suppl :S8-11
Dusso, Adriana S; Brown, Alex J; Slatopolsky, Eduardo (2005) Vitamin D. Am J Physiol Renal Physiol 289:F8-28
Cozzolino, Mario; Lu, Yan; Sato, Tetsuhiko et al. (2005) A critical role for enhanced TGF-alpha and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease. Am J Physiol Renal Physiol 289:F1096-102