Brown A J, Ritter C S, Finch J L, Slatopolsky E A
Renal Division, Washington University Medical School, St. Louis, Missouri, USA.
Kidney Int. 1999 Apr;55(4):1284-92. doi: 10.1046/j.1523-1755.1999.00386.x.
The abnormal control of parathyroid hormone secretion in chronic renal failure is attributed, in part, to down-regulation of the calcium-sensing receptor (CaR) in hyperplastic parathyroid tissue. The cause of this down-regulation is unknown. Here we examined the roles of uremia and parathyroid hyperplasia on parathyroid gland (PTG) CaR expression in the rat model of renal failure.
Rats made uremic by 5/6 nephrectomy were maintained for one month on diets containing 0.2% P (low phosphate), 0.5% P (normal phosphate) or 1.2% P (high phosphate); intact rats (controls) were maintained on the normal-phosphate diet.
CaR mRNA was reduced only in uremic rats fed the high-phosphate diet (55% less than in controls, P < 0.05). Immunohistochemical staining revealed decreased CaR protein expression in uremic high-phosphate rat PTG compared with controls (41% decrease as determined by computer-assisted quantitation, P < 0.01). PTG size was increased in uremic rats fed the high-phosphate diet compared with controls (2.77 +/- 0.95 vs. 0.77 +/- 0.16 microgram/g body wt, P < 0.0001). There was no increase in PTG size in uremic rats fed the low-phosphate and normal-phosphate diets (0.92 +/- 0.31 and 1.01 +/- 0.31 micrograms/g) compared with controls (0.77 +/- 0.16 microgram/g body wt). Immunohistochemical staining for proliferating cell nuclear antigen in hyperplastic PTG from uremic rats showed that CaR was decreased primarily in areas of active cell proliferation.
These results suggest that CaR down-regulation cannot be attributed to uremia per se, but rather, is associated with parathyroid cell proliferation. Furthermore, dietary phosphate restriction prevents both the parathyroid hyperplasia and decreased CaR expression in renal failure.
慢性肾衰竭中甲状旁腺激素分泌的异常调控部分归因于增生的甲状旁腺组织中钙敏感受体（CaR）的下调。这种下调的原因尚不清楚。在此，我们在肾衰竭大鼠模型中研究了尿毒症和甲状旁腺增生对甲状旁腺（PTG）CaR表达的作用。
通过5/6肾切除术造成尿毒症的大鼠在含0.2%磷（低磷）、0.5%磷（正常磷）或1.2%磷（高磷）的饮食中维持1个月；完整大鼠（对照组）维持正常磷饮食。
仅在喂食高磷饮食的尿毒症大鼠中CaR mRNA减少（比对照组少55%，P < 0.05）。免疫组织化学染色显示，与对照组相比，尿毒症高磷大鼠PTG中CaR蛋白表达降低（计算机辅助定量测定降低41%，P < 0.01）。与对照组相比，喂食高磷饮食的尿毒症大鼠PTG大小增加（2.77±0.95对0.77±0.16微克/克体重，P < 0.0001）。与对照组（0.77±0.16微克/克体重）相比，喂食低磷和正常磷饮食的尿毒症大鼠PTG大小没有增加（0.92±0.31和1.01±0.31微克/克）。尿毒症大鼠增生PTG中增殖细胞核抗原的免疫组织化学染色显示，CaR主要在活跃细胞增殖区域减少。
这些结果表明，CaR下调不能归因于尿毒症本身，而是与甲状旁腺细胞增殖有关。此外，饮食磷限制可防止肾衰竭中的甲状旁腺增生和CaR表达降低。
