PDF(Pubmed)
Abstract：
Aldosterone modulates the activity of both epithelial (specifically renal) and non-epithelial cells. Binding to the mineralocorticoid receptor (MR), activates two pathways: the classical genomic and the rapidly activated non-genomic that is substantially modulated by the level of striatin. We hypothesized that disruption of MR\'s non-genomic pathway would alter aldosterone-induced cardiovascular/renal damage. To test this hypothesis, wild type (WT) and striatin heterozygous knockout (Strn+/-) littermate male mice were fed a liberal sodium (1.6% Na+) diet and randomized to either protocol one: 3 weeks of treatment with either vehicle or aldosterone plus/minus MR antagonists, eplerenone or esaxerenone or protocol two: 2 weeks of treatment with either vehicle or L-NAME/AngII plus/minus MR antagonists, spironolactone or esaxerenone. Compared to the WT mice, basally, the Strn+/- mice had greater (~26%) estimated renal glomeruli volume and reduced non-genomic second messenger signaling (pAkt/Akt ratio) in kidney tissue. In response to active treatment, the striatin-associated-cardiovascular/renal damage was limited to volume effects induced by aldosterone infusion: significantly increased blood pressure (BP) and albuminuria. In contrast, with aldosterone or L-NAME/AngII treatment, striatin deficiency did not modify aldosterone-mediated damage: in the heart and kidney, macrophage infiltration, and increases in aldosterone-induced biomarkers of injury. All changes were near-normalized following MR blockade with spironolactone or esaxerenone, except increased BP in the L-NAME/AngII model. In conclusion, the loss of striatin amplified aldosterone-induced damage suggesting that aldosterone\'s non-genomic pathway is protective but only related to effects likely mediated via epithelial, but not non-epithelial cells.
摘要：
醛固酮调节上皮细胞(特别是肾)和非上皮细胞的活性。与盐皮质激素受体（MR）结合，激活两种途径:经典基因组和快速激活的非基因组,其基本上由纹状体蛋白的水平调节。我们假设MR非基因组途径的破坏会改变醛固酮诱导的心血管/肾脏损害。为了检验这个假设，野生型（WT）和纹状体蛋白杂合子敲除（Strn/-）同窝雄性小鼠饲喂自由钠（1.6％Na）饮食，并随机分配至方案1：用媒介物或醛固酮加/减MR拮抗剂治疗3周，依普利酮或艾沙司酮或方案二：使用媒介物或L-NAME/AngII加/减MR拮抗剂治疗2周，螺内酯或esaxerenone。与WT小鼠相比，基础上，Strn+/-小鼠的估计肾小球体积更大(约26%),肾组织中的非基因组第二信使信号传导(pAkt/Akt比率)减少。为了应对积极的治疗，纹状体蛋白相关的心血管/肾脏损害仅限于醛固酮输注引起的体积效应:血压(BP)和蛋白尿显著升高.相比之下,醛固酮或L-NAME/AngII治疗，纹状体蛋白缺乏没有改变醛固酮介导的损伤：在心脏和肾脏，巨噬细胞浸润，醛固酮诱导的损伤生物标志物增加。使用螺内酯或伊沙雷酮进行MR阻断后，所有变化均接近正常化，除了L-NAME/AngII模型中的BP增加。总之,纹状体素的丢失放大了醛固酮诱导的损伤，这表明醛固酮的非基因组途径是保护性的，但仅与可能通过上皮介导的效应有关，但不是非上皮细胞。
