Androgen receptor pathway in rats with autosomal dominant polycystic kidney disease
Androgen receptor pathway in rats with autosomal dominant polycystic kidney disease
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DOI：
10.1681/asn.2004070595
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发表时间：
2005-07-01
影响因子：
13.6
通讯作者：
Grantham, J
中科院分区：
文献类型：
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作者：
Nagao, S;Kusaka, M;Grantham, J
雄激素与调节常染色体显性多囊肾病 (ADPKD) 的疾病升级有关。将激动剂二氢睾酮 (DHT) 和拮抗剂氟他胺 (FLT) 给予患有 ADPKD 的 Han:SPRD 大鼠，并评估雄激素受体 (AR) 丰度和激活对囊性肾增大和功能的作用。通过免疫印迹测定的 8 至 10 周龄 Cy/+ 雄性大鼠的肾脏 AR 丰度自然比同窝 +/+ 对照大鼠增加了四倍。在雄性Cy/+中，去势使AR丰度降低-89.4%，低于对照+/+，并且囊壁上皮细胞内的AR表达显着降低。 Cy/+雄性大鼠的去势还使肾脏重量通常增加了-49.7%，肾囊肿面积减少了-34.0%，血清尿素氮减少了-72.8%；通过DHT将这些指数恢复到去势前的水平。在 Cy/+ 雄性大鼠中，与未治疗的 +/+ 对照相比，FLT 给药使肾脏重量的增加减少了 -27.6%，血清尿素氮的增加减少了 -53.7%，AR 表达的增加减少了 -84.2%。 FLT 对雌性大鼠没有影响。磷酸细胞外信号调节激酶 1/2 (P-ERK) 和 B-Raf（丝裂原激活蛋白激酶途径中的关键中间体，在 Cy/+ 中异常升高）的免疫印迹表达不受去势和/或 DHT 或 FLT 给药的影响。 AR在雄激素缺乏大鼠的肾上皮细胞核中不表达，但在雄激素充足大鼠的大多数肾小管和壁囊肿细胞核中表达。在雄激素缺乏的Cy/+中，80.6%已进入细胞周期的肾上皮细胞（增殖细胞核抗原阳性）也表达P-ERK。在雄激素充足的大鼠中，增殖细胞核抗原阳性细胞共表达 AR (12.7%)、P-ERK (36.4%) 和 P-ERK + AR (45.0%)； 5.9%可能是受到其他有丝分裂机制的刺激。结论是，Han:SPRD 中雄激素通过 ERK1/2 依赖性和 ERK1/2 独立信号机制增强肾细胞增殖和囊肿增大。这表明细胞增殖的基础率在很大程度上是由ERK1/2信号传导决定的，并且雄激素具有累加效应。
Androgens have been implicated in mediating disease escalation in autosomal dominant polycystic kidney disease (ADPKD). Dihydrotestosterone (DHT), an agonist, and flutamide (FLT), an antagonist, were administered to Han:SPRD rats with ADPKD, and the role of androgen receptor (AR) abundance and activation on the enlargement and function of cystic kidneys was evaluated. Renal AR abundance determined by immunoblots in 8- to 10-wk-old Cy/+ male rats was naturally increased four-fold above that of littermate +/+ controls. In male Cy/+, castration decreased AR abundance below control +/+ by -89.4%, and AR expression within cyst mural epithelial cells was strikingly decreased. Castration of Cy/+ male rats also reduced the usual increases in kidney weight by -49.7%, kidney cyst area by -34.0%, and serum urea nitrogen by -72.8%; these indices were restored to precastration levels by DHT. In Cy/+ male rats, FLT administration reduced the increase in kidney weight by -27.6% and serum urea nitrogen by -53.7% and decreased the increment in AR expression by -84.2% in comparison with untreated +/+ controls. There was no effect of FLT in female rats. Immunoblot expression of phospho-extracellular signal-regulated kinase 1/2 (P-ERK) and B-Raf, key intermediates in the mitogen-activated protein kinase pathway that are abnormally elevated in Cy/+, was unaffected by castration and/or administration of DHT or FLT. AR was not expressed in renal epithelial cell nuclei of androgen-deficient rats but was displayed in most tubule and mural cyst cell nuclei of androgen-replete rats. In androgen-deficient Cy/+, 80.6% of renal epithelial cells that had entered the cell cycle (proliferating cell nuclear antigen positive) also expressed P-ERK. In androgen-replete rats, proliferating cell nuclear antigen-positive cells co-expressed AR (12.7%), P-ERK (36.4%), and P-ERK + AR (45.0%); 5.9% were probably stimulated by other mitogenic mechanisms. It is concluded that androgens potentiate renal cell proliferation and cyst enlargement through ERK1/2-dependent and ERK1/2-independent signaling mechanisms in Han:SPRD. It is suggested that the basal rate of cell proliferation is determined by ERK1/2 signaling to a major extent and that androgens have additive effects.