The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system
The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system
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DOI：
10.1073/pnas.96.13.7403
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发表时间：
1999-06-22
影响因子：
11.1
通讯作者：
Smithies, O
中科院分区：
文献类型：
--
作者：
Matsukawa, N;Grzesik, WJ;Smithies, O
利钠肽（NP），主要在心脏[心房（ANP）和B型（BNP）]、脑（CNP）和肾脏中产生这些功能由利钠肽受体A和B介导（NPRA和NPRB），其具有当受体结合配体时被刺激的胞质鸟苷酸环化酶结构域，更丰富表达的受体（NPRC或C型）具有短的胞质结构域，没有鸟苷酸环化酶活性。NPRC被认为是一种清除受体，尽管它可能具有额外的功能。为了测试NPRC如何影响心血管和肾脏系统，我们通过同源重组在小鼠中失活其基因（Npr3）。[I-125] ANP在缺乏NPRC的纯合子循环中的半衰期比野生型长三分之二，尽管杂合子和纯合子的血浆ANP和BNP水平接近野生型。杂合子和纯合子的浓缩尿液的能力逐渐降低，表现出轻度利尿，并且倾向于血容量耗尽。纯合子的血压比正常值低8 mmHg（1 mmHg = 133 Pa）。这些结果与NPRC的唯一心血管/肾功能是清除利钠肽，从而调节利钠肽系统的局部作用一致。出乎意料的是，Npr3-/-纯合子具有与骨转换显著增加相关的骨骼畸形。表型与NPRC的骨功能一致，即清除局部合成的CNP并调节其作用。我们得出结论，NPRC调节利钠肽在其靶器官的可用性，从而使利钠肽系统的活性能够适应特定的局部需求。
Natriuretic peptides (NPs), mainly produced in heart [atrial (ANP) and B-type (BNP)], brain (CNP), and kidney (urodilatin), decrease blood pressure and increase salt excretion, These functions are mediated by natriuretic peptide receptors A and B (NPRA and NPRB) having cytoplasmic guanylyl cyclase domains that are stimulated when the receptors bind ligand, A more abundantly expressed receptor (NPRC or C-type) has a short cytoplasmic domain without guanylyl cyclase activity. NPRC is thought to act as a clearance receptor, although it may have additional functions, To test how NPRC affects the cardiovascular and renal systems, we inactivated its gene (Npr3) in mice by homologous recombination. The half life of [I-125]ANP in the circulation of homozygotes lacking NPRC is two-thirds longer than in the wild type, although plasma levels of ANP and BNP in heterozygotes and homozygotes are close to the wild type. Heterozygotes and homozygotes have a progressively reduced ability to concentrate urine, exhibit mild diuresis, and tend to be blood volume depleted. Blood pressure in the homozygotes is 8 mmHg (1 mmHg = 133 Pa) below normal. These results are consistent with the sole cardiovascular/renal function of NPRC being to clear natriuretic peptides, thereby modulating local effects of the natriuretic peptide system, Unexpectedly, Npr3 -/- homozygotes have skeletal deformities associated with a considerable increase in bone turnover. The phenotype is consistent with the bone function of NPRC being to clear locally synthesized CNP and modulate its effects, We conclude that NPRC modulates the availability of the natriuretic peptides at their target organs, thereby allowing the activity of the natriuretic peptide system to be tailored to specific local needs.