RNAi inhibition of mineralocorticoid receptors prevents the development of cold-induced hypertension.
The objective was to determine whether the mineralocorticoid receptor (MR) plays a role in the initiation and development of cold-induced hypertension (CIH) by testing the hypothesis that the RNA interference (RNAi) inhibition of the MR attenuates CIH. The recombinant adeno-associated virus (AAV) carrying a short-hairpin small-interference RNA for MR (MRshRNA) or a scrambled sequence (ControlshRNA) was constructed. Six groups of albino mice were used (6 mice/group). Three groups were exposed to cold (6.7 degrees C), whereas the remaining three groups were kept at room temperature (RT; warm) as controls. In each temperature condition, three groups received an intravenous injection of MRshRNA, ControlshRNA, or virus-free PBS, respectively, before exposure to cold. The viral complexes (0.35 x 10(11) particles/mouse, 0.5 ml) or PBS (0.5 ml) was delivered into the circulation via the tail vein. The blood pressure (BP) of the mice treated with ControlshRNA or PBS increased significantly during exposure to cold, whereas the BP of the cold-exposed MRshRNA-treated mice did not increase and remained at the level of the control group kept at RT. Thus AAV delivery of MRshRNA prevented the initiation of CIH. MRshRNA significantly attenuated cardiac and renal hypertrophy. MRshRNA decreased the cold-induced increase in MR protein expression to the control level in the hypothalamus, kidneys, and heart, indicating an effective prevention of the cold-induced upregulation of MR. RNAi inhibition of MR resulted in significant decreases in the plasma level of norepinephrine, plasma renin activity, and plasma level of aldosterone in cold-exposed mice. MR played a critical role in the initiation and development of CIH. AAV delivery of MRshRNA may serve as a new approach for the prevention of cold-induced hypertension.
Sun
Zhongjie
Z
Dept. of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73034, USA. zhongjie-sun@ouhsc.edu
Bello-Roufai
Mahajoub
M
Wang
Xiuqing
X
D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D003080:Cold Temperature / Q000009:adverse effects; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D004326:Drinking; D004435:Eating; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006973:Hypertension / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000097:blood; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000097:blood; D013997:Time Factors; D014161:Transduction, Genetic; D014554:Urination; D014764:Viral Proteins / Q000096:biosynthesis
D034741:RNA, Small Interfering; D018161:Receptors, Mineralocorticoid; D014764:Viral Proteins; D000450:Aldosterone; D012083:Renin; D009638:Norepinephrine