Novel Estrogen Metabolites and Experimental Polycystic Kidney Disease

描述（申请人提供）：常染色体显性多囊肾病（ADPKD）是终末期肾脏疾病的重要病因。男性性别是肾功能更快丧失的危险因素，但与性别相关的风险机制尚不清楚。在汉族：SPRD大鼠ADPKD模型中也存在类似的性别二态性，雌性受到相对保护。该模型中的内分泌消融研究证实了雄激素的有害作用和雌激素（17b-estradiol, E2）的保护作用。临床上，雌激素治疗的使用受到内分泌和心血管不良影响的限制。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E2的许多有益作用。由于它们对雌激素受体的亲和力最小，因此它们在临床使用时似乎更安全。初步数据显示2-OHE （> 2-ME）对雄性汉族SPRD大鼠肾囊肿生长发育的限制，并为本研究将探索的保护机制提供线索。2-OHE治疗与肾小管上皮细胞（RTE）凋亡和增殖减少有关；低氧诱导因子-1a在肾脏中的表达降低；p21表达增加；哺乳动物雷帕霉素靶蛋白（mTOR）在男性囊性肾脏中的表达降低。假设：(1)2-OHE通过抑制血管生成来限制囊性小管间质纤维化的生长和发展；抑制RTE增殖；和/或诱导RTE细胞凋亡。这些影响部分与p21、Akt和mTOR信号系统的调节有关。(2) 2- ohe通过限制RTE增殖、凋亡和/或血管生成，在基因不同的模型（PCK大鼠和Pkd2小鼠模型）中限制管间质纤维化的囊性生长和发育。方法：在Han:SPRD大鼠模型中，采用体内和体外互补的方法来探索2- OHE的保护机制，以及与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：这些研究将探讨两性异形在ADPKD进展中的重要机制。确定临床可接受的药物治疗以减缓疾病的进展是最终目标。

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.