Inhibitory effect of uremic solutions on protein-DNA-complex formation of the vitamin D receptor and other members of the nuclear receptor superfamily.
Chronic renal failure is often associated with a resistance to the biologically active form of vitamin D(3), the nuclear hormone 1alpha, 25-dihydroxyvitamin D(3) (VD). The actions of VD are mediated by the vitamin D receptor (VDR), a ligand-dependent transcription factor that binds as a dimeric complex with the retinoid X receptor (RXR) to specific DNA binding sites in the promoter regions of primary VD responding genes, referred to as VD response elements (VDREs). It could be shown in this study that uremic solutions derived from ultrafiltrate from hemodialysis patients and dialysate from peritoneal dialysis patients had an inhibitory effect on the complex formation and ligand inducibility of VDR-RXR heterodimers on different VDRE types. This inhibition was attributed to the formation of Schiff bases between "reactive aldehydes" and lysine residues of the DNA binding domain (DBD) of the VDR, but point mutagenesis data of different lysine residues in this study could not confirm this idea. However, the inhibitory effect of uremic solutions could also be observed for the complex formation of other homo- or heterodimer forming nuclear receptors, whereas an as a monomer binding nuclear receptor did not appear to be affected. These results indicate that VDR is a target of substances in uremic solutions in vitro, but also to some extent other nuclear receptors (i.e., other endocrine signaling systems) may be affected by renal failure.
Institut für Physiologische Chemie I, Heinrich-Heine-Universität Düsseldorf, D-40001 Düsseldorf, Germany. toell@uni-duesseldorf.de
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Toell
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Degenhardt
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Grabensee
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Carlberg
D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D005810:Multigene Family; D016296:Mutagenesis; D010530:Peritoneal Dialysis / Q000009:adverse effects; D011732:Pyridoxal Phosphate / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000187:drug effects* / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D006435:Renal Dialysis / Q000009:adverse effects; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism; D014511:Uremia / Q000378:metabolism
D004268:DNA-Binding Proteins; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D011732:Pyridoxal Phosphate