Testosterone and 17β-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice.
Testosterone and 17β-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice.
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DOI：
10.1038/ki.2010.398
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发表时间：
2011-02
影响因子：
19.6
通讯作者：
Karl M
中科院分区：
文献类型：
--
作者：
Doublier S;Lupia E;Catanuto P;Periera-Simon S;Xia X;Korach K;Berho M;Elliot SJ;Karl M
足细胞损伤和细胞凋亡被认为在肾小球硬化症的发展中即使不是必需的也很重要。雌性雌激素受体基因敲除小鼠由于卵巢睾酮生成和分泌过多，在 9 个月大时会出现肾小球硬化症。在这里，我们研究了该小鼠模型中肾小球硬化的发病机制，以确定睾酮和/或 17β-雌二醇是否直接影响足细胞的功能和存活。这些小鼠的肾小球硬化症与结蛋白的表达和去氧肾上腺素（足细胞损伤和细胞凋亡的标志物）的丢失有关。卵巢切除术通过消除内源性睾酮产生的来源来保留足细胞的功能和存活。相反，补充睾酮会诱导切除卵巢的野生型小鼠的足细胞凋亡。重要的是，足细胞表达功能性雄激素和雌激素受体，它们在各自配体的刺激下产生相反的作用。睾酮通过雄激素受体激活在体外诱导足细胞凋亡，但不依赖于 TGF-β1 信号通路。 17β-雌二醇预处理可防止睾酮诱导的足细胞凋亡（一种通过激活 ERK 信号通路介导的雌激素受体依赖性效应），并保护足细胞免受 TGF-β1 或 TNF-α 诱导的细胞凋亡。因此，足细胞是睾酮和 17β-雌二醇的靶细胞。这些激素调节足细胞损伤和细胞凋亡。
Podocyte damage and apoptosis are thought to be important if not essential in the development of glomerulosclerosis. Female estrogen receptor knockout mice develop glomerulosclerosis at 9 months of age due to excessive ovarian testosterone production and secretion. Here, we studied the pathogenesis of glomerulosclerosis in this mouse model to determine whether testosterone and/or 17β-estradiol directly affect the function and survival of podocytes. Glomerulosclerosis in these mice was associated with the expression of desmin and the loss of nephrin, markers of podocyte damage and apoptosis. Ovariectomy preserved the function and survival of podocytes by eliminating the source of endogenous testosterone production. In contrast, testosterone supplementation induced podocyte apoptosis in ovariectomized wild-type mice. Importantly, podocytes express functional androgen and estrogen receptors, which, upon stimulation by their respective ligands, have opposing effects. Testosterone induced podocyte apoptosis in vitro by androgen receptor activation, but independent of the TGF-β1 signaling pathway. Pretreatment with 17β-estradiol prevented testosterone-induced podocyte apoptosis, an estrogen receptor-dependent effect mediated by activation of the ERK signaling pathway, and protected podocytes from TGF-β1- or TNF-α-induced apoptosis. Thus, podocytes are target cells for testosterone and 17β-estradiol. These hormones modulate podocyte damage and apoptosis.