EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Journal of the American Society of Nephrology (Impact Factor: 9.34). 03/2008; 19(2):310-20. DOI: 10.1681/ASN.2007040406
Source: PubMed


Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-alpha is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of parathyroid TGF-alpha, the progression of growth, and the reduction of VDR. Increased TGF-alpha/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-beta, in human hyperplastic parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-beta transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-alpha activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.

Download full-text


Available from: Ignacio González-Suárez, Jul 23, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Long lasting hypocalcemia, hyperphosphatemia, low calcitriol and high fibroblast growth factor 23 could result in progressive parathyroid gland hyperplasia with high, uncontrolled, parathormone production, e.g. severe secondary hyperparathyroidism (sHPT), in 10% of dialysis patients. Parathyroidectomy (PTX) could be a solution, but has inherent (low) surgical risks and although dramatically decreases parathormone levels, could induce hypoparathyroidism (50-66%) and low turnover bone disease. Moreover, the rate of recurrences is 15-20% at 10 years. Total and subtotal PTX with autografting are equally safe and effective with similar recurrences rates. Calcimimetics are efficient drugs, but with limited effectiveness in sHPT, as only 25% of patients responded to cinacalcet. In the USA, they are more cost-effective than PTX only in patients with >2 years expected dialysis duration. As there are not randomized studies to compare surgical to medical therapy, the strength of evidence allows only for suggestions in guidelines. In countries like Romania, where dialysis vintage is high because of the low transplantation rate and calcimimetics are costly, PTX seems a better solution when parathyroid glands are large (diameter >1cm or total mass >500mg), parathormone levels >800pg/mL, in patients who are not candidates for renal transplantation or are anticipated to stay >2 years on dialysis.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Affinity alkylating derivatives of naturally occurring molecules were originally developed to target and probe the substrate/ligand-binding sites of enzymes and receptors. These reagents, by virtue of their ability to covalently attach to the substrate/ligand-binding pockets of target enzymes/receptors, provide valuable structural information of the host and the guest, focusing on the dynamic interaction between the two. Our laboratory developed affinity and photoaffinity labeling derivatives of 1,25-dihydroxyvitamin D3 [1,25(OH)2D] to probe the ligand-binding domain of nuclear vitamin D receptor (VDR). With these studies we obtained crucial information about the ligand contact points and three-dimensional geometry of the ligand-binding domain of VDR, in relation to the biological properties of 1,25(OH)2D. 1,25(OH)2D is an anticancer agent, albeit with severe toxicity at pharmacological doses. We observed that an affinity alkylating derivative of 1,25(OH)2D strongly inhibits the growth of various cancer cells and causes these cells to undergo apoptosis, demonstrating strong potential of this affinity analog of 1,25(OH)2D as an anticancer agent. This article summarizes the results of various studies involving affinity alkylating derivatives of vitamin D metabolites to investigate structural–functional aspects of VDR, as well as development of these reagents as potential therapeutic agents in cancer.
  • [Show abstract] [Hide abstract]
    ABSTRACT: A solution growth process is employed for the deposition of CdS1 − xSex thin film composites with 0 ≤x≤ 1. Cadmium acetate, thiourea and sodium selenosulphate were used as the basic source materials. The samples were obtained at 55 °C in an alkaline medium and were characterised by optical and electrical characterisation techniques. The layer thickness is found to be decreased as x is varied from 0 to 1. The optical absorption studies showed a high coefficient of absorption (α = 104 cm−1) with an allowed direct type of transition. The optical energy gap decreases continuously (typically from 2.42 eV to 1.74 eV) as x is increased from 0 to 1. For values of x between 0.5 and 0.8, two absorption edges have been observed; one at approximately 2.40 eV corresponding to the fundamental optical transitions in CdS and the other decreasing continuously, which corresponds to the fundamental transitions in CdS1 − xSex solid solution. The electrical conductivity is found to decrease up to x = 0.5 and to increase thereafter for further increase in x. The activation energy is more or less the same for all compositions and has no systematic dependence on the composition parameter x.
    Materials Chemistry and Physics 02/1997; 47(2-3):263-267. DOI:10.1016/S0254-0584(97)80062-4 · 2.26 Impact Factor
Show more