Renal hyporesponsiveness to atrial natriuretic peptide in congestive heart failure results from reduced atrial natriuretic peptide receptor concentrations
Renal hyporesponsiveness to atrial natriuretic peptide in congestive heart failure results from reduced atrial natriuretic peptide receptor concentrations
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DOI：
10.1152/ajprenal.00418.2006
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发表时间：
2007-05-01
影响因子：
4.2
通讯作者：
Potter, Lincoln R.
中科院分区：
文献类型：
--
作者：
Bryan, Paula M.;Xu, Xin;Potter, Lincoln R.
心房钠尿肽 (ANP) 和 B 型钠尿肽通过激活钠尿肽受体 A (NPR-A)（一种跨膜鸟苷酸环化酶，也称为鸟苷酸环化酶 A）来降低血压和心脏肥大。NPR-A 失活是充血性心力衰竭 (CHF) 中观察到的肾脏反应性低下的潜在机制，但缺乏支持这一假设的直接数据。我们检查了 CHF 中 NPR-A 活性是否降低，如果是，是通过什么机制降低的。在两项独立的试验中，通过 8 周的横向主动脉缩窄在小鼠中诱发 CHF。假手术对照组接受无收缩手术。收缩的动物出现严重的心力衰竭，表现为心脏重量增加、左心室舒张末期和收缩期直径增加以及左心室射血分数降低。测定肾膜的鸟苷酸环化酶活性或用于通过顺序免疫沉淀/SDS-PAGE纯化NPR-A。在两项独立试验中，CHF 动物肾膜中最大 ANP 依赖性鸟苷酸环化酶活性降低了 44% 或 43%。第二次试验中基础环化酶活性也降低了 31%。 CHF 动物肾膜中磷酸化 NPR-A 的量也减少了 25% 或 24%。 SYPRO Ruby 染色表明，第一个试验中各处理之间的 NPR-A 蛋白水平相似。然而，第二次试验中通过免疫沉淀/Western 分析对 NPR-A 蛋白水平进行更准确的估计表明，NPR-A 蛋白降低了 30%。我们得出的结论是 NPR-A 蛋白水平降低，而不是受体去磷酸化，解释了 CHF 中肾脏对利尿钠肽的反应性低下。
Atrial natriuretic peptide ( ANP) and B- type natriuretic peptide decrease blood pressure and cardiac hypertrophy by activating natriuretic peptide receptor A ( NPR- A), a transmembrane guanylyl cyclase also known as guanylyl cyclase A. Inactivation of NPR- A is a potential mechanism for the renal hyporesponsiveness observed in congestive heart failure ( CHF) but direct data supporting this hypothesis are lacking. We examined whether NPR- A activity was reduced in CHF, and if so, by what mechanism. In two separate trials, CHF was induced in mice by 8- wk transverse aortic constriction. Sham controls underwent surgery without constriction. The constricted animals developed severe heart failure as indicated by increased heart weight, increased left ventricular end diastolic and systolic diameters, and decreased left ventricular ejection fractions. Kidney membranes were assayed for guanylyl cyclase activity or used to purify NPR- A by sequential immunoprecipitation/ SDS- PAGE. Maximal ANP- dependent guanylyl cyclase activities were reduced by 44 or 43% in kidney membranes from CHF animals in two independent trials. Basal cyclase activities were also reduced by 31% in the second trial. The amount of phosphorylated NPR- A was reduced by 25 or 24% in kidney membranes from CHF animals as well. SYPRO Ruby staining suggested that NPR- A protein levels were similar between treatments in the first trial. However, more accurate estimates of NPR- A protein levels by immunoprecipitation/ Western analysis in the second trial indicated that NPR- A protein was reduced by 30%. We conclude that reduced NPR- A protein levels, not receptor dephosphorylation, explain the renal hyporesponsiveness to natriuretic peptides in CHF.