Lins Bruna Bezerra, Casare Fernando Augusto Malavazzi, Fontenele Flávia Ferreira, Gonçalves Guilherme Lopes, Oliveira-Souza Maria
Laboratory of Renal Physiology, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Front Physiol. 2021 Apr 1;12:642752. doi: 10.3389/fphys.2021.642752. eCollection 2021.
High plasma angiotensin II (Ang II) levels are related to many diseases, including hypertension, and chronic kidney diseases (CKDs). Here, we investigated the relationship among prolonged Ang II infusion/AT1 receptor (AT1R) activation, oxidative stress, and endoplasmic reticulum (ER) stress in kidney tissue. In addition, we explored the chronic effects of Ang II on tubular Na transport mechanisms. Male Wistar rats were subjected to sham surgery as a control or prolonged Ang II treatment (200 ng⋅kg⋅min, 42 days) with or without losartan (10 mg⋅kg⋅day) for 14 days. Ang II/AT1R induced hypertension with a systolic blood pressure of 173.0 ± 20 mmHg (mmHg, = 9) compared with 108.0 ± 7 mmHg (mmHg, = 7) in sham animals. Under these conditions, gene and protein expression levels were evaluated. Prolonged Ang II administration/AT1R activation induced oxidative stress and ER stress with increased Nox2, Nox4, and mRNA expression, phosphorylated PERK and eIF2α protein expression as well as mRNA expression. Ang II/AT1R also raised and mRNA expression, suggesting proinflammatory, and profibrotic effects. Regarding Na tubular handling, Ang II/AT1R enhanced cortical non-phosphorylated and phospho/S552/NHE3, NHE1, ENaC β, NKCC2, and NCC protein expression. Our results also highlight the therapeutic potential of losartan, which goes beyond the antihypertensive effect, playing an important role in kidney tissue. This treatment reduced oxidative stress and ER stress signals and recovered relevant parameters of the maintenance of renal function, preventing the progression of Ang II-induced CKD.
高血浆血管紧张素II（Ang II）水平与许多疾病相关，包括高血压和慢性肾脏病（CKD）。在此，我们研究了肾组织中Ang II长期输注/AT1受体（AT1R）激活、氧化应激和内质网（ER）应激之间的关系。此外，我们探讨了Ang II对肾小管钠转运机制的慢性影响。雄性Wistar大鼠接受假手术作为对照，或接受Ang II长期治疗（200 ng·kg·min，42天），同时或不同时给予氯沙坦（10 mg·kg·天），持续14天。与假手术动物的收缩压108.0±7 mmHg（mmHg，n = 7）相比，Ang II/AT1R诱导的高血压收缩压为173.0±20 mmHg（mmHg，n = 9）。在这些条件下，评估基因和蛋白质表达水平。Ang II长期给药/AT1R激活诱导氧化应激和ER应激，Nox2、Nox4和mRNA表达增加，磷酸化的PERK和eIF2α蛋白表达以及mRNA表达增加。Ang II/AT1R还提高了和mRNA表达，提示有促炎和促纤维化作用。关于肾小管钠处理，Ang II/AT1R增强了皮质非磷酸化和磷酸化/S552/NHE3、NHE1、ENaC β、NKCC2和NCC蛋白表达。我们的结果还突出了氯沙坦的治疗潜力，其作用超出了降压效果，在肾组织中发挥重要作用。这种治疗降低了氧化应激和ER应激信号，并恢复了维持肾功能的相关参数，防止了Ang II诱导的CKD进展。
