Dietary phosphorus (P) restriction is known to ameliorate secondary hyperparathyroidism in renal failure patients. In early renal failure, this effect may be mediated by an increase in 1,25-(OH) 2 D 3 , whereas in advanced renal failure, P restriction can act independent of changes in 1,25-(OH) 2 D 3 and serum ionized calcium (ICa). In this study, we examined the effects of dietary P on serum PTH, PTH mRNA, and parathyroid gland (PTG) hyperplasia in uremic rats. Normal and uremic rats were maintained on a low (0.2%) or high (0.8%) P diet for 2 mo. PTG weight and serum PTH were similar in both groups of normal rats and in uremic rats fed the 0.2% P diet. In contrast, there were significant increases in serum PTH (130 Ϯ 25 vs. 35 Ϯ 3.5 pg/ml, P Ͻ 0.01), PTG weight (1.80 Ϯ 0.13 vs. 0.88 Ϯ 0.06 g/gram of body weight, P Ͻ 0.01), and PTG DNA (1.63 Ϯ 0.24 vs. 0.94 Ϯ 0.07 g DNA/gland, P Ͻ 0.01) in the uremic rats fed the 0.8% P diet as compared with uremic rats fed the 0.2% P diet. Serum ICa and 1,25-(OH) 2 D 3 were not altered over this range of dietary P, suggesting a direct effect of P on PTG function. We tested this possibility in organ cultures of rat PTGs. While PTH secretion was acutely (30 min) regulated by medium calcium, the effects of medium P were not evident until 3 h. During a 6-h incubation, PTH accumulation was significantly greater in the 2.8 mM P medium than in the 0.2 mM P medium (1,706 Ϯ 215 vs. 1,033 Ϯ 209 pg/ g DNA, P Ͻ 0.02); the medium ICa was 1.25 mM in both conditions. Medium P did not alter PTH mRNA in this system, but cycloheximide (10 g/ml) abolished the effect of P on PTH secretion. Thus, the effect of P is posttranscriptional, affecting PTH at a translational or posttranslational step. Collectively, these in vivo and in vitro results demonstrate a direct action of P on PTG function that is independent of ICa and 1,25-(OH) 2 D 3 . ( J. Clin. Invest. 1996. 97:2534-2540.)

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The role of hyperphosphatemia in the pathogenesis of secondary hyperparathyroidism, cardiovascular disease, and progression of renal failure is widely known. Here we studied effects of dietary phosphate restriction on mortality and vascular calcification in uremic rats. Control and uremic rats were fed a high-phosphate diet and at 3 months a portion of rats of each group were killed. Serum phosphate and the calcium phosphate product increased in uremic rats, as did aortic calcium. Of the rats, 56% had positive aortic staining for calcium (von Kossa), RUNX2, and osteopontin. The remaining uremic rats were continued on diets containing high phosphate without and with sevelamer, or low phosphate, and after 3 more months they were killed. Serum phosphate was highest in uremic rats on high phosphate. Serum PTH and FGF-23 were markedly lower in rats on low phosphate. Mortality on high phosphate was 71.4%, with sevelamer reducing this to 37.5% and phosphate restriction to 5.9%. Positive aortic staining for von Kossa, RUNX2, and osteopontin was increased, but phosphate restriction inhibited this. Kidneys from low-phosphate and sevelamer-treated uremic rats had less interstitial fibrosis, glomerulosclerosis, and inflammation than those of uremic rats on high phosphate. Importantly, kidneys from rats on low phosphate showed improvement over kidneys from high-phosphate rats at 3 months. Left ventricles from rats on low phosphate had less perivascular fibrosis and smaller cardiomyocyte size compared to rats on high phosphate. Thus, intensive phosphate restriction significantly reduces mortality in uremic rats with severe vascular calcification.

1,25-dihydroxyvitamin D3 11,25(OH)2D31 suppresses parathyroid hormone (PTH) gene transcription. Recent evidence suggests that retinoid X receptors are involved in 1,25(OH)2D3-mediated transcriptional events. However, little data exists for a role of retinoids in parathyroid function or in PTH expression. In the present study, we observed that all-trans-or 9-cis retinoic acid suppressed the release of PTH from bovine parathyroid cell cultures. Both retinoids were remarkably potent with significant decreases evident at 10-10 M and a maximally suppressive effect (-65%) at 10'-M. All-trans-retinol was considerably less potent in this system. The effect was not evident until 12 h, suggesting that retinoids did not affect the rapid secretion of preexisting PTH stores. PreproPTIH mRNA levels were also suppressed by retinoic acid and the retinoid potencies were similar to those observed in the secretion studies. Combined treatment with 10-6 M retinoic acid and 10-8 M 1,25(0H)2D3 more effectively decreased PTH secretion and preproPTH mRNA than did either compound alone. These data indicate that retinoic acid: (a) elicits a bioresponse in bovine parathyroid cells; (b) attenuates PTH expression at the protein and mRNA levels, and (c) acts independently of 1,25(OH)2D3 in the control of PTH expression. (J. Clin. Invest. 1994. 93:725-730.)