Estrogens do not protect, but androgens exacerbate, collagen accumulation in the female mouse kidney after ureteric obstruction
Estrogens do not protect, but androgens exacerbate, collagen accumulation in the female mouse kidney after ureteric obstruction
复制标题
DOI：
10.1016/j.lfs.2016.06.022
复制
发表时间：
2016-08-01
期刊：
影响因子：
6.1
通讯作者：
Samuel, Chrishan S.
中科院分区：
文献类型：
--
作者：
Hewitson, Tim D.;Boon, Wah Chin;Samuel, Chrishan S.
目的：慢性肾脏疾病进展的性别基础存在争议。不幸的是，大多数针对这个问题的实验研究没有区分雌激素的直接作用和通过芳香酶将睾酮转化为17 β-雌二醇而间接激活雌激素受体。我们研究了雌性芳香酶敲除（ArKO）小鼠肾纤维化的发病机制，所述小鼠缺乏循环和储存的雌激素，而具有正常水平的睾酮。主要方法：将ArKO小鼠和它们的野生型（ArWT）对应小鼠进行单侧输尿管梗阻（UUO），在UUO后第0、3和9天收集肾组织。还研究了5 α-二氢睾酮（DHT）给药对每种基因型的影响。对组织进行生物化学和组织化学纤维化评估。Western印迹分析用于测量α-平滑肌肌动蛋白（α-SMA）表达和TGF-β 1信号传导。基质金属蛋白酶-2（MMP-2）活性通过酶谱法测定。关键发现：UUO随着时间的推移增加胶原含量（p < 0.05（D3）和p < 0.01（D9）vs第0天），在定性（胶原IV染色）和定量（羟脯氨酸浓度）分析中基因型之间没有差异。非芳香化DHT的全身给药增加胶原蛋白含量后3天的UUO在两种基因型。这并不被α-SMA（肌成纤维细胞负荷）或TGF-β 1信号传导的任何变化所掩盖，但与DHT降低两种基因型中MMP 2活性相当（p < 0.05 vs基因型对照）。在该模型中，雄激素而不是雌激素是参与调节疾病相关肾瘢痕形成的相关因素。(C)2016由Elsevier Inc.出版
Aims: Controversy surrounds the gender basis of progression in chronic kidney disease. Unfortunately, most experimental studies addressing this question do not distinguish between direct effects of estrogen and indirect activation of estrogen receptors through conversion of testosterone to 17 beta-estradiol by aromatase. We examined the pathogenesis of renal fibrosis in female aromatase knockout (ArKO) mice, which lack circulating and stored estrogens, while having normal levels of testosterone.Main methods: ArKO mice and their wild-type (ArWT) counterparts were subjected to unilateral ureteric obstruction (UUO), with kidney tissue collected at day(D) 0,3 and 9 post-UUO. Effects of 5 alpha-dihydrotestosterone (DHT) administration on each genotype were also studied. Tissue was assessed biochemically and histochemically for fibrosis. Western blot analysis was used to measure a-smooth muscle actin (alpha-SMA) expression and TGF-beta 1 signalling. Matrix metalloproteinase-2 (MMP-2) activity was measured by zymography.Key findings: UUO increased collagen content over time (p < 0.05 (D3) and p < 0.01 (D9) vs day 0), with no difference between genotypes in qualitative (collagen IV staining) and quantitative (hydroxyproline concentration) analyses. Systemic administration of non-aromatizable DHT increased collagen content after 3 days of UUO in both genotypes. This was not paralleled by any change in a-SMA (myofibroblast burden) or TGF-beta 1 signalling but was commensurate with DHT reducing MMP2 activity in both genotypes (p < 0.05 vs genotype controls).Significance: Physiological concentrations of estrogens do not protect the injured kidney from fibrosis progression. Androgens rather than estrogens are the relevant factor involved in regulating disease-related renal scarring in this model. (C) 2016 Published by Elsevier Inc.