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

描述（由申请人提供）： 心血管疾病是美国人死亡的主要原因。全身性动脉高血压（或简称“高血压”）是心血管疾病发展的主要危险因素。醛固酮和脱氧皮质酮（DOC）是盐皮质激素，可通过增加尿钠（Na）潴留引起高血压，并通过增加尿酸化引起低钾血症代谢紊乱。盐皮质激素影响远端肾单位和集合管（CD）离子转运，以实现这些效果。CD表达H，K-ATP酶的至少两种亚型，HK <$1和HK <$2，它们参与CD的酸分泌。我们最近的研究还表明，长期DOC新戊酸盐（DOCP）的管理刺激肾钠潴留，体重增加，代谢性贫血，这是依赖于H，K-ATP酶的存在。具体地，缺乏H，KATP酶（HK 1，2-/-）的小鼠在响应DOCP刺激时不能产生显著的Na保留或代谢性钠潴留。单HK <$1-/-与双HK <$1，2-/-的反应的比较强烈地表明H，K-ATP酶HK <$2亚型在对DOCP的反应中具有重要的生理作用。因此，我们的中心假设是：A）H，K-ATP酶HK <$2亚型对于盐皮质激素的慢性作用是至关重要的，盐皮质激素的慢性作用是产生肾钠潴留，引起低钾代谢性水肿和升高血压（BP）; B）饮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，这取决于H，K-ATP酶HK <$2亚型的诱导。2同种型在肾脏中。我们提出了以下具体目标：1）确定H，K-ATP酶HK <$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 <$2亚型在血压调节中的作用以及K摄入和低钾血症对这些变化的贡献; 3）确定WT和HK <$2亚型的差异是否与高钾血症有关。2 KO动物对DOCP给药的反应反映了肾表型。我们将测试新的生理假设，即H，K-ATP酶HK <$2亚型在钠稳态，容量调节和血压控制中具有重要作用。因此，我们已经开发了一种综合方法，结合整个动物代谢平衡研究，体外微灌注，最先进的BP无线电遥测测量和肾移植，以检查盐皮质激素刺激HK <$2的生理意义。

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.