INHIBITION OF NUCLEAR UPTAKE OF CALCITRIOL RECEPTOR BY UREMIC ULTRAFILTRATE

The biological action of calcitriol is mediated through a hormone-receptor complex interacting with nuclear chromatin. Interaction of the calcitriol receptor (VDR) with VDR response elements produces bioactive proteins which carry out the physiological actions of calcitriol. Since biological response to calcitriol appears to be diminished in renal failure, we studied the effect of uremic toxins on the interaction of VDR with nuclear chromatin using in vitro nuclear uptake of the H-3-calcitriol labeled VDR by intestinal nuclei. We found that nuclear uptake of the labeled intestinal VDR from renal failure rats was significantly lower than that from the control animals. HPLC fractionated uremic ultrafiltrate directly inhibited nuclear uptake of the labeled VDR when the labeled VDR was incubated with 50% of the ultrafiltrate for various time intervals ranging from 15 minutes to 6 hours. Infusion of uremic ultrafiltrate to normal rats for 20 hours also produced intestinal VDR with a lower binding affinity for intestinal nuclei when compared to the controls infused with normal ultrafiltrate. The latter study suggests that uremic toxins are responsible for the decreased nuclear uptake of VDR of rats with renal failure. Although it is difficult to extrapolate these results directly to the intact cells, our findings suggest that part of the calcitriol resistance in renal failure could be explained by decreased entry of receptor into the nucleus.