Abstract
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–1⋅min–1, 42 days) with or without losartan (10 mg⋅kg–1⋅day–1) for 14 days. Ang II/AT1R induced hypertension with a systolic blood pressure of 173.0 ± 20 mmHg (mmHg, n = 9) compared with 108.0 ± 7 mmHg (mmHg, n = 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, Cyba and Ncf1 mRNA expression, phosphorylated PERK and eIF2α protein expression as well as Atf4 mRNA expression. Ang II/AT1R also raised Il1b, Nfkb1 and Acta2 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.
Highlights
The renin-angiotensin system (RAS) activity triggers the octapeptide angiotensin II (Ang II) synthesis, which exerts its effects by binding to two distinct G-protein-coupled receptors, AT1 (AT1R) and AT2 (AT2R; Gubler and Antignac, 2010)
The results presented as the mean ± S.D. were analyzed by two-way analysis of variance (ANOVA) using GraphPad Prism 8.0 software (GraphPad Software, Inc., San Diego, CA, United States)
In addition to these findings, the present study revealed that the prolonged effect of Ang II/AT1 receptor (AT1R) on the endoplasmic reticulum (ER) stress response was mediated by increased PERK and eIF2α protein expression and activating transcription factor 4 (Atf4) mRNA expression and increased eIF2α protein expression
Summary
The renin-angiotensin system (RAS) activity triggers the octapeptide angiotensin II (Ang II) synthesis, which exerts its effects by binding to two distinct G-protein-coupled receptors, AT1 (AT1R) and AT2 (AT2R; Gubler and Antignac, 2010). High plasma levels of Ang II are often related to hypertension, renal damage and cardiac fibrosis. In this context, AT1R antagonists are known for their therapeutic effects on cardiovascular and renal disorders, as well diabetes (Villapol and Saavedra, 2015). We showed that Ang II (200 ng·kg−1·min−1) infusion over 2 weeks, which activated AT1R, induced severe preglomerular vascular injury, decreased renal vascular resistance, and increased renal plasma flow (RPF) and GFR, consistent with outward preglomerular remodeling, as well as albuminuria, glomerulosclerosis, and natriuresis (Casare et al, 2016). Ang II involvement on oxidative stress, endoplasmic reticulum (ER) stress or tubular Na+ transporters were not investigated
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