title: Chronic NF-κB blockade improves renal angiotensin II type 1 receptor functions and reduces blood pressure in Zucker diabetic rats.
abstract: 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.
authors.affiliation: The Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China. lh060608@163.com.|Chongqing Institute of Cardiology, Chongqing, PR China. lh060608@163.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Luo
authors.affiliation: The Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China. 213474962@qq.com.|Chongqing Institute of Cardiology, Chongqing, PR China. 213474962@qq.com.
authors.forename: Xinquan
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China. 575565291@qq.com.|Chongqing Institute of Cardiology, Chongqing, PR China. 575565291@qq.com.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China. ccy19740920@163.com.|Chongqing Institute of Cardiology, Chongqing, PR China. ccy19740920@163.com.
authors.forename: Caiyu
authors.initials: C
authors.lastname: Chen
authors.affiliation: The Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China. 12826305@qq.com.|Chongqing Institute of Cardiology, Chongqing, PR China. 12826305@qq.com.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: The Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China. 316296487@qq.com.|Chongqing Institute of Cardiology, Chongqing, PR China. 316296487@qq.com.
authors.forename: Zaicheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: The Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China. 919335951@qq.com.|Chongqing Institute of Cardiology, Chongqing, PR China. 919335951@qq.com.
authors.forename: Shuo
authors.initials: S
authors.lastname: Chen
authors.affiliation: The Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China. cyzeng01@163.com.|Chongqing Institute of Cardiology, Chongqing, PR China. cyzeng01@163.com.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zeng
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2; D004231:Diuresis / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009318:Natriuresis / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D060888:Real-Time Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016328:NF-kappa B; D011759:Pyrrolidines; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; C081643:candesartan