Association between the Y chromosome and androgens

临床研究的累积证据表明，不同病因的肾脏疾病在男性中比年龄匹配的女性更普遍。此外，男性非糖尿病慢性肾脏疾病的进展速度比女性快，与血压无关。这些观察结果表明，遗传和/或激素男性特异性因素可能会对人类的肾功能和结构产生不利影响。然而，尚未在男性中进行Y染色体和雄激素与肾脏表型之间关系的联合分析。根据我们的初步和以前报道的研究，我们假设，人类Y染色体内的遗传变异，至少部分通过调节雄激素的循环浓度，对男性的肾功能和结构产生不利影响。1.使用两个表型良好的波兰男性队列，我们将确定Y染色体非重组区（NRY）多态性与人类雄激素水平和肾功能的相关性（具体目标1）。将使用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对NRY内HindIII（+/-）双等位基因标记进行基因分型。将通过放射免疫测定法评估游离睾酮、脱氢表雄酮、硫酸脱氢表雄酮和双氢睾酮的血清浓度。将使用肌酐清除率和尿白蛋白/肌酐比值评价肾功能。2.我们将使用来自因肾癌而接受单侧选择性肾切除术的人肾未受累部分的肾组织，检查NRY与雄激素水平和肾结构的关系（具体目标2）。将通过光学显微镜评估肾脏结构变化。分别通过增殖细胞核抗原和末端脱氧核苷酸转移酶生物素-dUTP缺口末端标记（TUNEL）测定细胞增殖和死亡。将通过免疫组织化学和I型和IV型胶原定位和表达的Western分析评估细胞外基质沉积。确定本申请中提出的NRY、雄激素和人肾功能和结构之间的关联将提高我们对慢性肾脏疾病的患病率和进展中的性二态性的理解，以及对这些疾病过程的预防和治疗方案的开发。

Accumulating evidence from clinical studies suggest that renal diseases of different etiologies are more prevalent among men than age-matched women. Furthermore, non-diabetic chronic renal diseases progress more rapidly in men than women, independently of blood pressure. These observations suggest that genetic and/or hormonal male-specific factors may adversely affect renal function and structure in humans. However, a joint analysis of the relationships between the Y chromosome and androgens with respect to renal phenotypes has not been performed in men. Based on our preliminary and previously reported studies, we hypothesize that genetic variation within the human Y chromosome acting, at least in part, through modulation of circulating concentrations of androgens have detrimental effects on renal function and structure in men. 1. Using two well-phenotyped cohorts of Polish men, we will determine the association of polymorphisms in the non-recombining region of the Y chromosome (NRY) with androgen levels and renal function in humans (Specific Aim 1). Genotyping of the Hindlll(+/-) bi-allelic marker within the NRY will be performed using the polymerase chain reaction - restriction fragment length polymorphisms (PCR-RFLP) method. Serum concentrations of free testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and dihydrotestosterone will be assessed by radioimmunoassay. Renal function will be evaluated using creatinine clearance and urinary albumin-to-creatinine ratio. 2. Using renal tissue from the unaffected part of the human kidney of men undergoing unilateral elective nephrectomy due to renal cancer, we will examine the association of the NRY with androgen Ievels and renal structure (Specific Aim 2). Renal structural changes will be assessed by light microscopy. Cell proliferation and death will be determined by proliferating cell nuclear antigen and Terminal Deoxynucleotidyl Transferase Biotin-dUTP Nick End labeling (TUNEL), respectively. Extracellular matrix deposition will be assessed by immunohistochemistry and Western analysis of collagen types I and IV localization and expression. Determination of the association among NRY, androgens and human renal function and structure proposed in this application will improve our understanding of sexual dimorphism in prevalence and progression of chronic renal disorders and development of preventive and therapeutic regimens for these disease processes.