Calcimimetic Inhibits Late-Stage Cyst Growth in ADPKD
Calcimimetic Inhibits Late-Stage Cyst Growth in ADPKD
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DOI：
10.1681/asn.2008090927
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发表时间：
2009-07-01
影响因子：
13.6
通讯作者：
Moe, Sharon M.
中科院分区：
文献类型：
--
作者：
Gattone, Vincent H., II;Chen, Neal X.;Moe, Sharon M.
在多囊肾病(PKD)中，多囊蛋白1和2的基因突变导致细胞内钙转运缺陷，从而减少细胞内钙并改变cAMP信号以利于增殖。我们假设，钙感应受体的变构调节剂--仿钙剂，会通过增加细胞内钙来减少囊泡的生长。我们随机将20周龄常染色体显性遗传性PKD(杂合子Cy/+)雄性大鼠分为四组：(1)不治疗组；(2)饮食中配制的拟钙剂R-568；(3)R-568加补钙饮用水(R-568+Ca)；或(4)正常饮食补钙饮用水(Ca)。在34到38周期间，三个治疗组中的任何一个治疗组的PKD严重程度都没有进展。与不治疗相比，在34周时，所有处理组的囊泡生长没有受到影响，但在38周时，囊腔体积和纤维化程度较低，两个R-568处理组显示出比单独钙处理组更大的减少。在34-38周期间，对照组(P<；0.001)和钙组(P<；0.01)的总肾脏重量分别增加了78%和19%，但R-568或R-568加钙组没有增加，这表明尽管甲状旁腺激素受到同等的抑制，但疾病的进展仍受到抑制。综上所述，甲状旁腺功能亢进症的治疗阻止了啮齿类囊性肾病的晚期进展。R-568本身的好处表明，钙敏感受体的调节可能通过直接调节细胞内钙而对晚期囊泡生长产生额外的抑制作用。
In polycystic kidney disease (PKD), genetic mutations in polycystin 1 and 2 lead to defective intracellular trafficking of calcium, thereby decreasing intracellular calcium and altering cAMP signaling to favor proliferation. We hypothesized that calcimimetics, allosteric modulators of the calcium-sensing receptor, would reduce cyst growth by increasing intracellular calcium. We randomly assigned 20-wk-old male rats with a form of autosomal dominant PKD (heterozygote Cy/+) to one of four groups for 14 to 18 wk of treatment: (group 1) no treatment; (group 2) calcimimetic R-568 formulated in the diet; (group 3) R-568 plus calcium-supplemented drinking water (R-568 plus Ca); or (group 4) Ca-supplemented drinking water with a normal diet (Ca). Severity of PKD did not progress in any of the three treatment groups between 34 and 38 wk. Compared with no treatment, cyst growth was unaffected at 34 wk by all treatments, but cyst volume and fibrosis were lower at 38 wk, with both R-568-treated groups demonstrating a greater reduction than calcium alone. Between 34 and 38 wk, the total kidney weight increased by 78% in the control group (P < 0.001) and by 19% in the Ca group (P < 0.01), but did not increase in the R-568 or R-568 plus Ca groups, suggesting inhibition of disease progression despite equivalent suppression of parathyroid hormone. In summary, treatment of hyperparathyroidism halts late-stage progression of rodent cystic kidney disease. The benefit of R-568 alone suggests calcium-sensing receptor modulation may have additional inhibitory effects on late-stage cyst growth resulting from a direct modulation of intracellular calcium.