Chronic NF-κB blockade improves renal angiotensin II type 1 receptor functions and reduces blood pressure in Zucker diabetic ratsReport as inadecuate




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Cardiovascular Diabetology

, 14:76

First Online: 10 June 2015Received: 23 March 2015Accepted: 02 June 2015

Abstract

BackgroundBoth angiotensin II type 1 receptor AT1R and nuclear factor-kappa B NF-κB play significant roles in the pathogenesis of hypertension and type 2 diabetes. However, the role of NF-κB in perpetuating renal AT1 receptors dysfunction remains unclear. The aim of the present study to determine whether blockade of NF-κB, could reverse the exaggerated renal AT1R function, reduce inflammatory state and oxidative stress, lower blood pressure in Zucker diabetic fatty ZDF rats.

MethodsPyrrolidine dithiocarbamate PDTC, a NF-κB inhibitor 150 mg-kg in drinking wateror vehicle was administered orally to 12-weeks-old ZDF rats and their respective control lean Zucker LZ rats for 4 weeks. Blood pressure was measured weekly by tail-cuff method. AT1R functions were determined by measuring diuretic and natriuretic responses to AT1R antagonist candesartan; 10 μg-kg-min iv. The mRNA and protein levels of NF-κB, oxidative stress maker and AT1R were determined using quantitative real-time PCR and Western blotting, respectively. The NF-κB-DNA binding activity in renal cortex was measured by Electrophoretic mobility shift assay EMSA.

ResultsAs compared with LZ rats, ZDF rats had higher blood pressure, impaired natriuresis and diuresis, accompanied with higher levels of oxidative stress and inflammation. Furthermore, AT1R expression was higher in renal cortex from ZDF rats; candesartan induced natriresis and diuresis, which was augmented in ZDF rats. Treatment with PDTC lowered blood pressure and improved diuretic and natriuretic effects in ZDF rats; meanwhile, the increased oxidative stress and inflammation were reduced; the increased AT1R expression and augmented candesartan-mediated natriuresis and diuresis were recoverd in ZDF rats. Our further study investigated the mechanisms of PDTC on AT1R receptor expression. It resulted that PDTC inhibited NF-κB translocation from cytosol to nucleus, inhibited binding of NF-κB with AT1R promoter, therefore, reduced AT1R expression and function.

ConclusionsOur present study indicates blockade of NF-κB, via inhibition of binding of NF-κB with AT1R promoter, reduces renal AT1R expression and function, improves oxidative stress and inflammatory-anti-inflammatory balance, therefore, lowers blood pressure and recovers renal function in ZDF rats.

KeywordsAngiotensin II type 1 receptor Inflammatory Oxidative stress Nuclear factor-kappa B Hypertension AbbreviationsNF-κBNuclear factor-kappa B

AT1R`Angiotensin II type 1 receptor

ZDFZucker diabetic fatty

LZLean Zucker

PDTCPyrrolidine dithiocarbamate

RASRenin-angiotensin-aldosterone system

ANG IIAngiotensin II

PVNParaventricular nucleus

GRK4G-protein–coupled receptor kinase 4

EMSAElectrophoretic mobility shift assay

TNF-αNecrosis factor-alpha

IL-6Interleukin-6

Hao Luo and Xinquan Wang contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s12933-015-0239-7 contains supplementary material, which is available to authorized users.

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Author: Hao Luo - Xinquan Wang - Jialiang Wang - Caiyu Chen - Na Wang - Zaicheng Xu - Shuo Chen - Chunyu Zeng

Source: https://link.springer.com/article/10.1186/s12933-015-0239-7







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