Long-Term Angiotensin II Infusion Induces Oxidative and Endoplasmic Reticulum Stress and Modulates Na+ Transporters Through the Nephron

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.

Inhibition of angiotensin II type 1 receptor reduces oxidative stress damage to the intestinal barrier in severe acute pancreatitis

“…AT1-mediated oxidative stress injury has been extensively reported in the literature. 25,26 Our experiment provided compelling evidence that AT1 was highly expressed in intestinal epithelial mucosa, and its mediated oxidative stress response was involved in intestinal mucosal barrier injury. At the same time, it was observed that by inhibiting AT1, the expression of TJ protein, GSH and SOD in intestinal mucosa epithelium were improved.…”

Heart Failure and Cardiorenal Syndrome: A Narrative Review on Pathophysiology, Diagnostic and Therapeutic Regimens—From a Cardiologist’s View

“…CysC is a cysteine proteinase inhibitor that might aid in overcoming some of the limitations related to the use of Cr serum levels for the estimation of GFR. Moreover, these levels are less dependent on body mass, nutritional status, or age [ 50 , 51 ]. However, the relatively high cost of measuring CysC, when compared to Cr, contributes to its still limited use in routine clinical practice.…”

Fibrosis, the Bad Actor in Cardiorenal Syndromes: Mechanisms Involved

“…Different pathologies, such as diabetes mellitus [ 340 ], obesity [ 341 , 342 ], cardiovascular disease [ 343 , 344 ] and CKD [ 345 , 346 ], have been associated with ER stress. In CRS, the activation of ER stress in the heart and kidney could be induced by different factors, such as hemodynamic changes, hormones from the RAAS, inflammation or oxidative stress [ 346 , 347 , 348 ].…”

“…Different pathologies, such as diabetes mellitus [ 340 ], obesity [ 341 , 342 ], cardiovascular disease [ 343 , 344 ] and CKD [ 345 , 346 ], have been associated with ER stress. In CRS, the activation of ER stress in the heart and kidney could be induced by different factors, such as hemodynamic changes, hormones from the RAAS, inflammation or oxidative stress [ 346 , 347 , 348 ]. These pathophysiological mediators could directly induce ER stress in the myocardium or renal parenchyma, resulting in apoptotic cell death due to prolonged UPR activation [ 349 , 350 , 351 ] and the consequent fibrotic wound formation, all of which would eventually lead to structural and functional changes [ 348 , 352 , 353 , 354 ].…”