The Effect of Angiotensin II on Chronic Renal Disease: Participation of NADPH Oxidase Enzymes, Endoplasmic Reticulum Stress and Tubular Na+ Transporters

Abstract

IntroductionChronic kidney disease (CKD) associated with hypertension is a serious disease of high incidence in the health system, and its progression may be associated with renal disorders induced by angiotensin II (Ang II). Thus, the objective of this study was to investigate the mechanisms by which Ang II participates in renal injury associated with CKD, considering the contribution of the NADPH oxidase enzymatic complex to the generation of reactive oxygen species (ROS) and the associated factors with of endoplasmic reticulum (ER) stress, as well as the changes in the tubular sodium (Na+) transporters expression.MethodsMale Wistar rats weighting between 150 and 200 g were treated with Ang II (200 ng/kg/min, by osmotic mini pump, model 2006, ALZET) for 42 days and/or losartan (10 mg/kg/day per gavage) for 14 days and organized into four groups: Control; Treated with Ang II; Treated with losartan and co‐treated with Ang II / losartan. During treatment, the tail blood pressure was evaluated. After treatment, the total renal tissue was used for gene expression analyzes by real‐time polymerase chain reaction (qPCR) and protein expression by western blotting. Immunohistochemistry and immunofluorescence staining were evaluated in the kidney cortex. Statistical analysis was assessed by one‐way ANOVA followed by the Bonferroni's test. Significance was assumed at p<0.05.ResultsThe results indicate that in Ang II chronic treatment induced significant increase in mRNA expression for Nox2 (p<0.01 vs CTL), Nox4 (p<0.01 vs CTL), p22phox (p<0.01 vs CTL), p47phox (p<0.001 vs CTL), Atf4 (p<0.05 vs CTL) and eIF2α (p<0.05 vs CTL), and protein expression of NOX2 (p<0.01 vs CTL), eIF2α (p<0.05 vs CTL) and PERK (p<0.001 vs CTL). Ang II also induced increased protein expression of Na+ exchangers NHE1 (p<0.01 vs CTL) and NHE3 (p<0.05 vs CTL), co‐transporters NKCC2 (p<0.001 vs CTL) and NCC (p<0.01 vs CTL), also Na+ epithelial channel ENaC α isoform in the medulla (p<0.001 vs CTL) and β isoform in cortex (p<0.01 vs CTL). Furthermore, the all stimulatory effects of Ang II were decreased by co‐treatment with losartan.Conclusionour results suggest that the chronic infusion of Ang II was able to stimulate the expression of mRNA to factors associated with ER stress and oxidative stress which may be related with increased expression of NHE1, NHE3, NKCC2, NCC and ENaC (α and β subunits).Support or Funding InformationCNPq (140141/2016‐2), CAPES, FAPESP.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.