INHIBITION OF NUCLEAR UPTAKE OF CALCITRIOL RECEPTOR BY UREMIC ULTRAFILTRATE

The biological action of calcitriol is mediated through a hormone-rece ptor complex interacting with nuclear chromatin. Interaction of the ca lcitriol receptor (VDR) with VDR response elements produces bioactive proteins which carry out the physiological actions of calcitriol. Sinc e 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-ca lcitriol labeled VDR by intestinal nuclei. We found that nuclear uptak e of the labeled intestinal VDR from renal failure rats was significan tly lower than that from the control animals. HPLC fractionated uremic ultrafiltrate directly inhibited nuclear uptake of the labeled VDR wh en the labeled VDR was incubated with 50% of the ultrafiltrate for var ious time intervals ranging from 15 minutes to 6 hours. Infusion of ur emic ultrafiltrate to normal rats for 20 hours also produced intestina l VDR with a lower binding affinity for intestinal nuclei when compare d 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 s uggest that part of the calcitriol resistance in renal failure could b e explained by decreased entry of receptor into the nucleus.