Novel Estrogen Metabolites and Experimental Polycystic Kidney Disease

新型雌激素代谢物与实验性多囊肾病

• 批准号: 7585984
• 负责人: SHARON ANDERSON
• 金额: $ 15.75万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585984
• 关键词: 2-hydroxyestradiol; 2-methoxyestradiol; Ablation; Adverse effects; Affect; Affinity; Androgens; Angiogenesis Inhibition; Apoptosis; Attenuated; Autosomal Dominant Polycystic Kidney; Biological Preservation; Cardiovascular system; Chronic Kidney Failure; Clinical; Cyclin-Dependent Kinase Inhibitor; Cystic kidney; Data; Disease; Disease Progression; End stage renal failure; Endocrine; Epithelial Cell Proliferation; Epithelial Cells; Estradiol; Estrogen Receptors; Estrogen Therapy; Estrogens; Female; Fibrosis; Gender; Genetic; Goals; Grant; Growth and Development function; Hypoxia Inducible Factor; In Vitro; Induction of Apoptosis; Interruption; Intervention; Kidney; Kidney Diseases; Kidney Failure; Metabolite Interaction; Methods; Modeling; Pathway interactions; Pharmaceutical Preparations; Polycystic Kidney Diseases; Process; Rattus; Renal function; Risk; Risk Factors; Rodent Model; Signal Transduction; Sirolimus; System; Testing; Tubular formation; Up-Regulation; angiogenesis; efficacy testing; in vivo; mTOR protein; male; mouse model; neoplastic cell; novel; protective effect; public health relevance; sexual dimorphism

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.

描述（由申请方提供）：常染色体显性多囊肾病（ADPKD）是终末期肾病的重要原因。男性是肾功能更快丧失的风险因素，但性别相关风险的机制尚不清楚。在Han：SPRD大鼠ADPKD模型中也存在类似的性二态性，雌性动物相对受到保护。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（17 b-雌二醇，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E2的许多有益作用。由于它们对雌激素受体的亲和力很小，因此它们在临床使用中显得更安全。初步数据表明2-OHE（> 2-ME）对雄性Han：SPRD大鼠肾囊肿生长和发育的限制，并提供了保护机制的线索，本研究将探讨这一机制。2-OHE治疗被发现与减少肾小管上皮细胞（RTE）凋亡和增殖;减少缺氧诱导因子-1a的肾表达;增加p21的表达;和减少表达的哺乳动物雷帕霉素靶蛋白（mTOR），在囊性男性肾脏。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。这些作用部分与p21、Akt和mTOR信号系统的调节有关。(2)2-OHE通过限制RTE增殖和凋亡和/或血管生成，限制了遗传学不同模型（PCK大鼠和Pkd 2小鼠模型）中肾小管间质纤维化的囊性生长和发展。研究方法：在Han：SPRD大鼠模型中，将使用互补的体内和体外方法探索2- OHE的保护机制以及与p21、Akt和mTOR通路的相互作用。还将在PCK大鼠和Pkd 2小鼠模型中检测2-OHE的保护作用。意义：这些研究将探讨ADPKD进展中性别二型性的重要机制。确定临床上可接受的药物治疗以减缓疾病进展是最终目标。 公共卫生相关性： 常染色体显性遗传性多囊肾病（ADPKD）是肾衰竭最常见的遗传原因，男性比女性受影响更严重。雌激素的新代谢物似乎可以减缓雄性大鼠模型中ADPKD的进展，而没有雌激素治疗所见的严重副作用。确定这些药物保护肾脏的机制可能使我们能够设计新的药理学方法，这些方法在减缓临床肾脏疾病的进展方面是安全有效的。