Renal 11b-Hydroxysteroid Dehydrogenases and Hypertension

肾 11b-羟基类固醇脱氢酶与高血压

• 批准号: 7480343
• 负责人: MINGYU LIANG
• 金额: $ 34.1万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480343
• 关键词: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenases; 11p; Address; Animal Model; Applications Grants; Attenuated; Blood Pressure; Controlled Study; Corticosterone; DNA; Dahl Hypertensive Rats; Data; Development; Diet; Distal; Functional disorder; Genes; Glucocorticoids; Goals; Human; Hydroxysteroid Dehydrogenases; Hypertension; Immunohistochemistry; Kidney; Knock-out; Laboratories; Laboratory Finding; Liquid substance; Messenger RNA; Micropuncture; Microsatellite Repeats; Modeling; Molecular; Molecular Analysis; Mus; Mutation; Natural regeneration; Northern Blotting; Organ; Pathway interactions; Physiological; Polymerase Chain Reaction; Prevention; Protein Isoforms; Protein Overexpression; Rat Strains; Rattus; Relative (related person); Renal Hypertension; Renal Tissue; Research; Research Design; Research Personnel; Role; Series; Small Interfering RNA; Sodium Chloride; Techniques; Testing; Time; Tissues; Transgenic Organisms; Tubular formation; Urine; Western Blotting; base; blood pressure regulation; consomic; design; hypertension treatment; improved; in vivo; inhibitor/antagonist; innovation; instrument; kidney medulla; novel; protein expression; salt sensitive; trait; urinary

DESCRIPTION (provided by applicant): The overall goal of this grant proposal is to advance the understanding of the pathophysiology of salt-sensitive hypertension by investigating the role of renal 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11beta-HSDs are critical controllers of local levels of active glucocorticoids. Alterations of 11beta-HSDs that cause local excess of glucocorticoids in the kidney or other tissues (e.g., transgenic over-expression of the glucocorticoid-regenerating isoform 11beta-HSDI) result in hypertension. However, the importance of 11beta- HSDs in common forms of hypertension remains unclear. The Dahl salt-sensitive (SS) rat is a widely used model of human salt-sensitive hypertension. The consomic SS-13BN rat is genetically highly similar to SS, but has substantially reduced blood pressure salt-sensitivity. Previous studies from this laboratory found that 11beta-HSDI was over-expressed in the renal medulla (a kidney region critical for long-term blood pressure regulation) of SS compared to SS-13BN when rats were exposed to a high-salt diet. The proposed studies will test the hypothesis that dysregulation of renal medullary 11beta-HSD1 contributes to the development of salt-sensitive hypertension in SS rats. Studies are designed to: 1) characterize the expression and localization of 11beta-HSDI and related genes in SS and SS-13BN rats; 2) utilize in vivo small interfering RNA techniques to selectively suppress the expression of renal medullary 11beta-HSDI, which is not achievable with common pharmacological inhibitors, and examine the effect of such suppression on salt-induced hypertension in chronically instrumented SS rats; 3) begin to examine the functional mechanism for the role of 11beta-HSDI in salt-sensitive hypertension by investigating the effect of 11beta-HSDI suppression on renal tubular segmental fluid reabsorption in SS rats using micropuncture. Preliminary data has demonstrated the feasibility of the proposed studies and appeared to support the hypothesis. These studies will combine innovative molecular analysis/manipulation and functional assessment in genetically defined or modified animal models. The results are expected to elucidate a novel aspect of the pathophysiology of salt- sensitive hypertension and to provide potential new targets for prevention and treatment of hypertension.

描述（由申请人提供）：该赠款提案的总体目标是通过研究肾脏11Beta-Hydroxteroid脱氢酶（11BETA-HSD）的作用来提高对盐敏感高血压的病理生物生物生物的理解。 11BETA-HSD是活性糖皮质激素局部水平的关键控制器。在肾脏或其他组织中导致局部过量糖皮质激素过量的11BETA-HSD的改变（例如，糖皮质激素再生的同工型11beta-HSDI的转基因过表达）导致高血压。但是，在共同形式的高血压形式中，11BETA-HSD的重要性尚不清楚。 DAHL盐敏感（SS）大鼠是人类盐敏感高血压的广泛使用的模型。 Consomic SS-130亿只大鼠在遗传上与SS高度相似，但血压盐敏感性大大降低。该实验室的先前研究发现，与SS 130亿相比，当大鼠暴露于高盐饮食时，SS的肾脏髓质（对长期血压调节至关重要的肾脏区域）的表达过高。拟议的研究将检验以下假设：肾脏髓质11BETA-HSD1的失调有助于SS大鼠盐敏感高血压的发展。研究的设计为：1）表征SS和SS-130亿大鼠中11BETA-HSDI和相关基因的表达和定位； 2）利用体内小干扰RNA技术来选择性地抑制肾脏髓质11Beta-HSDI的表达，这在常见的药理抑制剂中是无法实现的，并检查了这种抑制对长期仪器仪器中盐诱导的高血压的影响； 3）开始研究11BETA-HSDI在盐敏感高血压中的作用，通过研究11BETA-HSDI抑制对使用微函数在SS大鼠中肾小管节液液的影响。初步数据证明了所提出的研究的可行性，似乎支持了这一假设。这些研究将结合创新的分子分析/操纵和在遗传定义或修饰的动物模型中的功能评估。预计该结果将阐明盐敏感高血压病理生理学的新方面，并为预防和治疗高血压提供潜在的新靶标。