Novel Estrogen Metabolites and Experimental Polycystic Kidney Disease

描述(申请人提供)：常染色体显性遗传性多囊肾病(ADPKD)是终末期肾脏疾病的重要原因。男性性别是肾功能快速丧失的危险因素，但与性别相关的风险机制尚不清楚。在HAN：SPRD大鼠ADPKD模型中也存在类似的性二型性，因为雌性相对受到保护。该模型的内分泌消融研究证实了雄激素的有害作用和雌激素(17b-雌二醇，E_2)的保护作用。在临床上，雌激素治疗的使用受到内分泌和心血管不良反应的限制。新的雌二醇代谢物，包括2-甲氧基雌二醇(2-ME)及其前体2-羟基雌二醇(2-OHE)，提供了许多雌二醇的有益作用。由于它们对雌激素受体的亲和力最小，临床使用似乎更安全。初步数据表明，2-OHE(&gt；2-ME)限制了雄性HAN：SPRD大鼠肾囊肿的生长和发育，并为本研究将探索的保护机制提供了线索。2-OHE治疗与减少肾小管上皮细胞(RTE)的凋亡和增殖，减少肾脏低氧诱导因子-1a的表达，增加p21的表达，以及减少哺乳动物雷帕霉素靶标(MTOR)的表达有关。假设：(1)2-OHE通过抑制血管生成、抑制RTE增殖和/或诱导RTE凋亡来限制肾小管间质纤维化的囊性生长和发展。这些效应部分与p21、Akt和mTOR信号系统的调制有关。(2)2-OHE通过限制RTE的增殖和凋亡和/或血管生成，在基因不同的模型中限制肾小管间质纤维化的囊性生长和发展：PCK大鼠和PKD2小鼠模型。方法：采用体内和体外互补的方法，探讨2-OHE对HAN：SPRD大鼠模型的保护机制及其与p21、Akt和mTOR通路的相互作用。2-OHE的保护作用也将在PCK大鼠和PKD2小鼠模型中进行测试。意义：这些研究将探索性二形性在ADPKD进展中的重要机制。确定临床上可接受的药物治疗以减缓疾病的进展是最终目标。 公共卫生相关性： 常染色体显性遗传性多囊肾病(ADPKD)是导致肾衰竭的最常见的遗传原因，男性比女性更严重。在雄性大鼠模型中，雌激素的新代谢物似乎可以减缓ADPKD的进展，而没有雌激素治疗所见的严重副作用。识别这些药物保护肾脏的机制可能使我们能够设计出新的药理方法，这些方法在减缓临床肾脏疾病的进展方面是安全有效的。

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of end-stage renal disease. Male gender is a risk factor for faster loss of renal function, but mechanisms of gender-related risk are not well understood. There is similar sexual dimorphism in the Han:SPRD rat model of ADPKD, in that females are relatively protected. Endocrine ablation studies in this model confirm the deleterious effect of androgens, and the protective effects of estrogen (17b-estradiol, E2). Clinically, use of estrogen therapy is limited by adverse endocrine and cardiovascular effects. Novel estradiol metabolites, including 2- methoxyestradiol (2-ME) and its precursor 2-hydroxyestradiol (2-OHE), provide many of the beneficial actions of E2. Since they have minimal affinity for the estrogen receptor, they appear safer for clinical use. Preliminary data indicate limitation of renal cyst growth and development by 2-OHE (> 2-ME) in male Han:SPRD rats, and offer clues as to mechanisms of protection which will be explored in this grant. 2-OHE therapy was found to be associated with decreased renal tubular epithelial cell (RTE) apoptosis and proliferation; decreased renal expression of hypoxia-inducible factor-1a; increased expression of p21; and reduced expression of the mammalian target of rapamycin (mTOR), in cystic male kidneys. Hypotheses: (1) 2-OHE limits cystic growth and development of tubulointerstitial fibrosis by inhibition of angiogenesis; suppression of RTE proliferation; and/or induction of RTE apoptosis. These effects relate, in part, to modulation of the p21, Akt, and mTOR signaling systems. (2) 2-OHE limits cystic growth and development of tubulointerstitial fibrosis in genetically dissimilar models: the PCK rat and Pkd2 mouse models, by limiting RTE proliferation and apoptosis, and/or angiogenesis. Methods: Complementary in vivo and in vitro approaches will be used to explore protective mechanisms of 2- OHE, and interactions with the p21, Akt, and mTOR pathways, in the Han:SPRD rat model. Protective effects of 2-OHE will also be tested in the PCK rat and Pkd2 mouse models. Significance: These studies will investigate important mechanisms underlying sexual dimorphism in progression of ADPKD. Identification of clinically acceptable pharmacologic treatments to slow the progression of disease is the ultimate goal. PUBLIC HEALTH RELEVANCE: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure, and males are more seriously affected than females. Novel metabolites of estrogen appear to slow progression of ADPKD in a male rat model, without the serious side effects seen with estrogen therapy. Identification of the mechanisms by which these drugs protect the kidney may enable us to devise new pharmacologic approaches, which are safe and effective in slowing the progression of clinical kidney disease.