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Mechanism of decreased intestinal calcitriol receptor concentration in renal failure
C H Hsu1, S R Patel, R Vanholder
1Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109.
Abstract:
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.
Insights
Uremic toxins impair calcitriol's biological actions by inhibiting its receptor's DNA interaction and reducing receptor synthesis. This affects vitamin D's role in renal failure patients.
Area of Science:
- Endocrinology
- Nephrology
- Molecular Biology
Background:
- Calcitriol (active vitamin D) action is mediated by its receptor binding to DNA.
- Inhibition of this interaction may reduce calcitriol's biological effects and receptor synthesis.
Purpose of the Study:
- To investigate the effect of uremic ultrafiltrate on calcitriol receptor interaction with DNA.
- To determine if uremic toxins influence calcitriol receptor synthesis and function.
Main Methods:
- DNA-cellulose chromatography to analyze receptor-DNA binding.
- In vitro experiments using uremic ultrafiltrate.
- Measurement of intestinal calcitriol receptor concentration in rats.
Main Results:
- Uremic ultrafiltrate reduced calcitriol receptor interaction with DNA in vitro.
- Chronic renal failure or uremic ultrafiltrate infusion resulted in a weaker DNA-binding receptor peak.
- Uremic ultrafiltrate decreased intestinal calcitriol receptor concentration and suppressed calcitriol-induced receptor upregulation.
Conclusions:
- Uremic toxins interfere with calcitriol receptor's ability to bind DNA.
- Uremic toxins reduce calcitriol receptor synthesis and its response to calcitriol.
- These mechanisms likely contribute to reduced calcitriol biological action in renal failure.