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

摘要

Background Both 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. Methods Pyrrolidine dithiocarbamate (PDTC), a NF-κB inhibitor (150?mg/kg in drinking water)or 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). Results As 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. Conclusions Our 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.