INHIBITION OF CALCITRIOL RECEPTOR-BINDING TO VITAMIN-D RESPONSE ELEMENTS BY UREMIC TOXINS

The genomic action of calcitriol (1,25-dihydroxy-vitamin D-3) is media ted through the interaction of the calcitriol receptor (VDR) with vita min D response elements (VDREs), Although renal failure is associated with resistance to the action of calcitriol, the mechanism of this res istance is not well understood. Therefore, we used the electrophoretic mobility shift assay to compare the ability of VDRs from normal and r enal failure rats to bind to the osteocalcin gene VDRE. The results in dicate that VDRs from renal failure rats have only half the DNA bindin g capacity as VDRs from control rats, despite identical calcitriol bin ding, Furthermore, incubation of normal VDRs with a uremic plasma ultr afiltrate resulted in a loss of > 50% of the binding sites for the ost eocalcin VDRE, When VDRs bound to DNA as heterodimers with retinoid X receptors, the inhibitory effect of the uremic ultrafiltrate was due t o a specific interaction with the VDR, not retinoid X receptors. In ad dition, uremic ultrafiltrate blocked calcitriol-induced reporter gene activity in transfected JEG-3 cells. Taken together, the results indic ate that an inhibitory effect of a uremic toxin(s) on VDR-VDRE binding could underlie the calcitriol resistance of renal failure.