Mechanism of decreased intestinal calcitriol receptor concentration in renal failure.
The biological actions of calcitriol and its receptor synthesis are believed to be mediated through the calcitriol-receptor complex interacting with nuclear chromatin of target cells. Thus inhibition of the receptor interaction with DNA could diminish the biological actions of calcitriol and upregulation of its receptor. We found that uremic ultrafiltrate reduced the receptor interaction with DNA in vitro. DNA-cellulose chromatography showed that the receptor from normal rats and rats infused with normal ultrafiltrate eluted as a single peak at 0.22 M KCl, whereas chronic renal failure rats and rats infused with uremic ultrafiltrate had two receptor peaks, i.e., one of normal activity at 0.22 M KCl and the other of weak activity at 0.12 M KCl. Furthermore, infusion of uremic ultrafiltrate to normal rats reduced the intestinal calcitriol receptor concentration (397 +/- 15.8 vs. 307 +/- 15.4 fmol/mg protein, both n = 4, P < 0.005). Uremic ultrafiltrate also suppressed the calcitriol-induced upregulation of the receptor (816 +/- 34.6 vs. 606 +/- 35.3 fmol/mg protein, P < 0.005). It appears that uremic toxins may reduce the biological action of calcitriol in renal failure by inhibiting receptor synthesis and the interaction of the hormone-receptor complex with nuclear chromatin.
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109.
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Hsu
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Patel
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Vanholder
D000818:Animals; D002482:Cellulose / Q000031:analogs & derivatives; D002846:Chromatography, Affinity; D004247:DNA / Q000378:metabolism; D007421:Intestine, Small / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D014511:Uremia / Q000378:metabolism
C033190:DNA-cellulose; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D002482:Cellulose; D004247:DNA