Role of H,K-ATPase in the Action of Mineralocorticoids

H,K-ATP 酶在盐皮质激素作用中的作用

• 批准号: 8762426
• 负责人: Charles S Wingo
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762426
• 关键词: Acids; Affect; Aftercare; Aldosterone; Alkalosis; Animals; Arts; Attenuated; Blood Pressure; Blood Volume; Blood gas; Body Weights and Measures; Cardiovascular Diseases; Cause of Death; Chronic; Collaborations; Data; Deoxycorticosterone; Development; Diet; Disease; Distal; Duct (organ) structure; Eating; Electrolyte Balance; Electrolyte Disorder; Electrolytes; Enzymes; Equilibrium; Excretory function; Exhibits; Fluid Balance; General Population; H(+)-K(+)-Exchanging ATPase; Health; Homeostasis; Hormones; Hypertension; Hypokalemia; In Situ Hybridization; In Vitro; Incidence; Intake; Intercalated Cell; Internal carotid artery structure; Intervention; Ion Transport; Kidney; Kidney Transplantation; Laboratories; Measurement; Mediating; Metabolic; Mineralocorticoids; Mus; Nephrons; Patients; Pharmacotherapy; Phenotype; Physiological; Plasma; Population; Potassium; Protein Isoforms; Proteins; Proton Pump; Proton-Translocating ATPases; Protons; Publishing; Regulation; Research; Risk Factors; Role; Sodium; Stroke; Telemetry; Testing; Transplantation; United States; Urine; Veterans; Water consumption; Weight Gain; Wild Type Mouse; Work; absorption; blood pressure regulation; cell type; design; mRNA Expression; novel; research study; response; salt balance; urinary

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death in the United States. Systemic arterial hypertension (or simply "hypertension") is a major risk factor for the development of cardiovascular disease. Aldosterone and desoxycorticosterone (DOC) are mineralocorticoids that cause hypertension through increased urinary sodium (Na) retention and hypokalemic metabolic alkalosis through greater urinary acidification. Mineralocorticoids affect distal nephron and collecting duct (CD) ion transport to achieve these effects. The CD expresses at least two isoforms of H,K-ATPases, HK¿1 and HK¿2, that participate in acid secretion by the CD. Our recent studies also show that chronic DOC pivalate (DOCP) administration stimulates renal Na retention, weight gain, and metabolic alkalosis that are dependent on the presence of H,K-ATPases. Specifically, mice that lack both H,KATPases (HK¿1,2 -/-) failed to develop significant Na retention or metabolic alkalosis in response to DOCP stimulation. Comparison of the response of the single HK¿1 -/- to the double HK¿1,2 -/- strongly suggests an important physiological role for the H,K-ATPase HK¿2 isoform in the response to DOCP. Therefore, our central hypotheses are that: A) the H,K-ATPase HK¿2 isoform is critical for the chronic action of mineralocorticoids to produce renal Na retention, cause hypokalemic metabolic alkalosis, and increase blood pressure (BP); and that B) dietary K loading abolishes or attenuates mineralocorticoid action on Na retention and electrolyte abnormalities, which are dependent on the induction of the H,K-ATPase HK¿2 isoform in the kidney. We propose the following specific aims: 1) to determine the role of the H,K-ATPase HK¿2 isoform in the ion transport response to chronic mineralocorticoid treatment; 2) to determine the role of H,K-ATPase HK¿2 isoform in the regulation of blood pressure and the contribution of K intake and hypokalemia to these changes; 3) to determine if the differences in WT and HK¿2 KO animals in response to DOCP administration reflect a renal phenotype. We will test the novel physiological hypothesis that the H,K-ATPase HK¿2 isoform has an important role in Na homeostasis, volume regulation and BP control. As such, we have developed an integrated approach that combines whole animal metabolic balance studies, in vitro microperfusion, state-ofthe- art radiotelemetry measurement of BP, and renal transplantation to examine the physiological significance of HK¿2 stimulation by mineralocorticoids.

描述（由申请人提供）： 心血管疾病是美国主要的死亡原因。 全身性动脉高血压（或简称“高血压”）是发生心血管疾病的主要危险因素。 (Na) 尿酸化增加导致的滞留和低钾性代谢性碱中毒影响远端肾单位和集合管。 (CD) 离子运输来实现这些效果 CD 表达至少两种 H,K-ATP 酶同工型 HK¿ 1和香港?? 2，参与 CD 的酸分泌，我们最近的研究还表明，长期给予 DOC 新戊酸 (DOCP) 会刺激肾钠潴留、体重增加和代谢性碱中毒，这取决于 H,K-ATP 酶的存在。缺乏两种 H,KATP 酶 (HK¿1,2 -/-) 的小鼠在对 DOCP 刺激的反应中未能显着出现钠潴留或代谢性碱中毒。 1 -/- 到双 HK¿ 1,2 -/- 强烈表明 H,K-ATPase HK 具有重要的生理作用¿ DOCP 反应中的 2 亚型因此，我们的中心假设是：A) H,K-ATPase HK¿ 2 同工型对于盐皮质激素产生肾钠潴留、导致低钾性代谢性碱中毒和血压升高 (BP) 的慢性作用至关重要；B) 膳食钾负荷消除或减弱盐皮质激素对钠潴留和电解质异常的作用，这些作用是依赖于 H,K-ATPase HK 的诱导¿我们提出以下具体目标：1) 确定 H,K-ATPase HK 的作用。 2亚型在慢性盐皮质激素治疗的离子转运反应中的作用；2)确定H,K-ATP酶HK的作用； 2 亚型在血压调节中的作用以及钾摄入和低钾血症对这些变化的影响 3) 确定 WT 和 HK 是否存在差异； 2 只 KO 动物对 DOCP 给药的反应反映了肾脏表型 我们将测试新的生理学假设，即 H,K-ATPase HK¿ 2 同工型在 Na 稳态、容量调节和血压控制中发挥着重要作用，因此，我们开发了一种综合方法，结合了整个动物代谢平衡研究、体外微灌注、最先进的血压无线电遥测测量和血压测量。肾移植检查HK的生理意义¿ 2 盐皮质激素刺激。