自发性高血压大鼠原发性肾脏 AT2 受体缺陷的鉴定。
- 作者列表："Kemp BA","Howell NL","Gildea JJ","Keller SR","Carey RM
RATIONALE:Previous studies identified a defect in Ang III (angiotensin III [des-aspartyl-angiotensin II])-elicited ATR (Ang type-2 receptor)-mediated natriuresis in renal proximal tubule cells of spontaneously hypertensive rats (SHR).,OBJECTIVE:This study aimed to delineate in prehypertensive SHR kidneys the receptor or postreceptor defect causing impaired ATR signaling and renal sodium (Na) retention by utilizing the selective ATR agonist compound-21 (C-21).,METHODS AND RESULTS:Female 4-week-old Wistar Kyoto and SHR rats were studied after 24-hour systemic ATR (Ang II type-1 receptor) blockade. Left kidneys received 30-minute renal interstitial infusions of vehicle followed by C-21 (20, 40, and 60 ng/[kg·min], each dose 30 minutes). Right kidneys received vehicle infusions. In Wistar Kyoto, C-21 dose-dependently increased urine Na excretion from 0.023±0.01 to 0.064±0.02, 0.087±0.01, and 0.089±0.01 µmol/min (=0.008, <0.0001, and <0.0001, respectively) and renal interstitial fluid levels of ATR downstream signaling molecule cGMP (cyclic guanosine 3',5' monophosphate) from 0.91±0.3 to 3.1±1.0, 5.9±1.2 and 5.3±0.5 fmol/mL (=nonsignificant, <0.0001, and <0.0001, respectively). In contrast, C-21 did not increase urine Na excretion or renal interstitial cGMP in SHR. Mean arterial pressure was slightly higher in SHR but within the normotensive range and unaffected by C-21. In Wistar Kyoto, but not SHR, C-21 induced ATR translocation to apical plasma membranes of renal proximal tubule cells, internalization/inactivation of NHE-3 (sodium-hydrogen exchanger-3) and Na/KATPase (sodium-potassium-atpase) and phosphorylation of ATR-cGMP downstream signaling molecules Src (Src family kinase), ERK (extracellular signal-related kinase), and VASP (vasodilator-stimulated phosphoprotein). To test whether cGMP could bypass the natriuretic defect in SHR, we infused 8-bromo-cGMP. This restored natriuresis, Na transporter internalization/inactivation, and Src and VASP phosphorylation, but not apical plasma membrane ATR recruitment. In contrast, 8-bromo-cAMP administration had no effect on natriuresis or ATR recruitment in SHR.,CONCLUSIONS:The results demonstrate a primary renal proximal tubule cell ATR natriuretic defect in SHR that may contribute to the development of hypertension. Since the defect is abrogated by exogenous intrarenal cGMP, the renal cGMP pathway may represent a viable target for the treatment of hypertension. Visual Overview: An online visual overview is available for this article.
理由: 以前的研究确定了 Ang III (血管紧张素 III [去天冬氨酰-血管紧张素 II]) 的缺陷-引起 ATR (Ang 2 型受体) 介导自发性高血压大鼠 (SHR) 肾近端小管细胞的利钠尿。,目的: 本研究旨在描述高血压前期 SHR 肾脏中导致 ATR 信号和肾钠 (Na) 受损的受体或受体后缺陷利用选择性 ATR 激动剂化合物-21 (C-21) 保留,方法和结果: 对雌性 4 周龄 Wistar Kyoto 和 SHR 大鼠进行了 24 小时全身 ATR (Ang ⅱ 1 型受体) 阻断后的研究。左肾接受 30 分钟肾间质内输注溶剂，然后 C-21 (20 、 40 和 60 ng/[kg · min]，每次剂量 30 分钟)。右肾接受溶剂输注。在 Wistar Kyoto，C-21 剂量依赖性增加尿 Na 排泄从 0.023 ± 0.01 到 0.064 ± 0.02，0.087 ± 0.01 和 0.089 ± 0.01 µ mol/min (= 0.008，<0.0001,和 <0.0001，分别) 和肾间质液水平的 ATR 下游信号分子 cGMP (环鸟苷 3 '，5' 一磷酸) 从 0.91 ± 0.3 到 3.1 ± 1.0, 5.9 ± 1.2 和 5.3 ± 0.5 fmol/mL (= 无显著性,分别 <0.0001 和 <0.0001)。相反，C-21 不增加 SHR 尿 Na 排泄或肾间质 cGMP。SHR 的平均动脉压略高，但在正常血压范围内，不受 C-21 影响。在 Wistar Kyoto，但不是 SHR，C-21 诱导 ATR 转位到肾近端小管细胞顶端质膜，内化/失活 NHE-3 (钠-氢交换体-3) 和 Na/KATPase (钠-钾-atp 酶) 和 ATR-cGMP 下游信号分子 Src (Src 家族激酶) 、 ERK (细胞外信号相关激酶) 的磷酸化,和 VASP (血管扩张刺激磷蛋白)。为了检测 cGMP 是否可以绕过 SHR 的利钠钠缺陷，我们输注了 8-溴-cGMP。这恢复了钠尿、 Na 转运蛋白内化/失活以及 Src 和 VASP 磷酸化，但没有恢复顶端质膜 ATR 募集。相比之下，8-溴-camp 给药对 SHR 的钠尿或 ATR 招募没有影响。,结论: 结果表明 SHR 的原发性肾近端小管细胞 ATR 钠尿肽缺陷可能与高血压的发生有关。由于外源性肾内 cGMP 可消除该缺陷，肾 cGMP 通路可能是治疗高血压的可行靶点。视觉概述: 本文提供了一个在线视觉概述。
METHODS:BACKGROUND:Hypertensive disorders of pregnancy (HDP) increase cardiovascular disease (CVD) risk. Pregnancy morbidities, including preeclampsia, and CVD are common in systemic lupus erythematosus (SLE). Possible connections are important to explore. In a population-based cohort, we investigated whether HDP is associated with a higher risk of cardiovascular outcomes separately in SLE and non-SLE to examine the role of SLE. METHODS:We identified first singleton births in the Medical Birth Register (1987-2012) among mothers with SLE and a large general population comparison group. Discharge diagnoses for HDP, cardiovascular outcomes, and hypertension in the Patient Register were identified using ICD codes. We estimated adjusted hazard ratios and 95% confidence intervals (HR, 95% CI) of the association between HDP and outcomes, in separate models in women with and without SLE. We then evaluated additive and multiplicative effect modification using relative excess risk due to interaction and Cox models jointly accounting for SLE and HDP, respectively. Mediation analysis estimated the proportion of the association between SLE and outcome explained by HDP. RESULTS:HDP were more common in SLE pregnancies (20% vs 7%). In SLE, HDP were associated with a two-fold higher rate of cardiovascular outcomes and three-fold higher rate of incident hypertension. HDP mediated 20% of the latter association. In women without SLE, HDP was associated with higher hypertension incidence later in life. CONCLUSION:In women with and without SLE, HDP were associated with a three-fold higher rate of hypertension. In SLE, women with HDP developed cardiovascular outcomes twice as often as women without HDP.
METHODS:BACKGROUND:'Neuronal precursor cell expressed developmentally down-regulated 4-like' (NEDD4L) is considered a candidate gene for hypertension-both functionally and genetically-through the regulation of the ubiquitination of the epithelial sodium channel (ENaC). This study explores the relationship between genetic variation in NEDD4L and hypertension with chronic kidney disease (CKD) in the southeastern Han Chinese population. METHODS:We recruited 623 CKD patients and measured ambulatory blood pressure monitoring (ABPM), and the rs4149601 and rs2288774 polymorphisms in NEDD4L were genotyped using qPCR. RESULTS:For rs4149601, significant differences in genotype frequencies in an additive model (GG vs GA vs AA) were observed between normotensive patients and hypertensive patients when hypertension was classified into ambulatory hypertension, clinical hypertension and ambulatory systolic hypertension (P = 0.038, 0.005 and 0.006, respectively). In a recessive model (GG+GA vs AA), the frequency of the AA genotype of rs4149601 in the hypertension groups were all higher than that in the normotensive groups. The genotype distribution of rs2288774 did not differ significantly between the normotensive and hypertensive patients. In both the full cohort and the propensity score matching (PSM) cohort, the AA genotype of rs4149601 (compared to the GG+GA genotype group) was independently correlated with ambulatory hypertension, clinical hypertension and ambulatory systolic hypertension by multivariate logistic regression analysis. CONCLUSIONS:The present study indicates that the AA genotype of rs4149601 associates with hypertension in CKD. Consequently, the rs4149601 A allele might be a risk factor for hypertension with CKD.
METHODS:BACKGROUND:The burden of hypertension in many low-and middle-income countries is alarming and requires effective evidence-based preventative strategies that is carefully appraised and accepted by key stakeholders to ensure successful implementation and sustainability. We assessed nurses' perceptions of a recently completed Task Shifting Strategy for Hypertension control (TASSH) trial in Ghana, and facilitators and challenges to TASSH implementation. METHODS:Focus group sessions and in-depth interviews were conducted with 27 community health nurses from participating health centers and district hospitals involved in the TASSH trial implemented in the Ashanti Region, Ghana, West Africa from 2012 to 2017. TASSH evaluated the comparative effectiveness of the WHO-PEN program versus provision of health insurance for blood pressure reduction in hypertensive adults. Qualitative data were analyzed using open and axial coding techniques with emerging themes mapped onto the Consolidated Framework for Implementation Research (CFIR). RESULTS:Three themes emerged following deductive analysis using CFIR, including: (1) Patient health goal setting- relative priority and positive feedback from nurses, which motivated patients to make healthy behavior changes as a result of their health being a priority; (2) Leadership engagement (i.e., medical directors) which influenced the extent to which nurses were able to successfully implement TASSH in their various facilities, with most directors being very supportive; and (3) Availability of resources making it possible to implement the TASSH protocol, with limited space and personnel time to carry out TASSH duties, limited blood pressure (BP) monitoring equipment, and transportation, listed as barriers to effective implementation. CONCLUSION:Assessing stakeholders' perception of the TASSH implementation process guided by CFIR is crucial as it provides a platform for the nurses to thoroughly evaluate the task shifting program, while considering the local context in which the program is implemented. The feedback from the nurses informed barriers and facilitators to implementation of TASSH within the current healthcare system, and suggested system level changes needed prior to scale-up of TASSH to other regions in Ghana with potential for long-term sustainment of the task shifting intervention. TRIAL REGISTRATION:Trial registration for parent TASSH study: NCT01802372. Registered February 27, 2013.