Stoll Danielle, Yokota Rodrigo, Sanches Aragão Danielle, Casarini Dulce E
Escola Paulista de Medicina - Department of Medicine, Nephrology Division, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil.
Physiol Rep. 2019 Jun;7(11):e14105. doi: 10.14814/phy2.14105.
The kidney is an important target of the renin-ANG-aldosterone system (RAAS). To date, several studies have demonstrated the existence of a local RAAS in various tissues, including the renal tissue. The mineralocorticoid aldosterone is known to play a critical role in the classical RAAS; however, its effect on mesangial cells (MCs) remains to be elucidated. Based on this, our aim was to investigate whether aldosterone stimulation can modulate the intracellular RAAS of immortalized human MCs by evaluating ANG-converting enzyme (ACE)/ANG II/ANG II receptor type 1 (AT1) and ANG-converting enzyme 2 (ACE2)/ANG (1-7)/MAS receptor axes. To realise this, protein expression, enzyme activity, and immunofluorescence were performed under aldosterone stimulation and in the presence of the mineralocorticoid receptor (MR) antagonist spironolactone (SPI). We observed that high doses of aldosterone increase ACE activity. The effect of aldosterone on the catalytic activity of ACE was completely abolished with the pretreatment of SPI suggesting that the aldosterone-induced cell injuries through ANG II release were attenuated. Aldosterone treatment also decreased the expression of MAS receptor, but did not alter the expression or the catalytic activity of ACE 2 and ANG (1-7) levels. Spironolactone modulated the localization of ANG II and AT1 receptor and decreased ANG (1-7) and MAS receptor levels. Our data suggest that both aldosterone and the MR receptor antagonist can modulate both of these axes and that spironolactone can protect MCs from the damage induced by aldosterone.
肾脏是肾素-血管紧张素-醛固酮系统（RAAS）的重要靶器官。迄今为止，多项研究已证实包括肾组织在内的多种组织中存在局部RAAS。已知盐皮质激素醛固酮在经典RAAS中起关键作用；然而，其对系膜细胞（MCs）的影响仍有待阐明。基于此，我们的目的是通过评估血管紧张素转换酶（ACE）/血管紧张素II/1型血管紧张素II受体（AT1）和血管紧张素转换酶2（ACE2）/血管紧张素（1-7）/MAS受体轴，研究醛固酮刺激是否能调节永生化人MCs的细胞内RAAS。为实现这一目标，在醛固酮刺激下并在存在盐皮质激素受体（MR）拮抗剂螺内酯（SPI）的情况下进行了蛋白质表达、酶活性和免疫荧光检测。我们观察到高剂量醛固酮会增加ACE活性。SPI预处理可完全消除醛固酮对ACE催化活性的影响，这表明醛固酮通过释放血管紧张素II诱导的细胞损伤得到了减轻。醛固酮处理还降低了MAS受体的表达，但未改变ACE 2和血管紧张素（1-7）水平的表达或催化活性。螺内酯调节了血管紧张素II和AT1受体的定位，并降低了血管紧张素（1-7）和MAS受体水平。我们的数据表明，醛固酮和MR受体拮抗剂均可调节这两个轴，且螺内酯可保护MCs免受醛固酮诱导的损伤。
