Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms
Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms
复制标题
DOI：
10.1073/pnas.0502236102
复制
发表时间：
2005-07-26
影响因子：
11.1
通讯作者：
Yanagihara, N
中科院分区：
文献类型：
--
作者：
Morishita, T;Tsutsui, M;Yanagihara, N
一氧化氮(NO)在几乎所有的组织器官中都有产生，在生理和病理条件下发挥着多种生物学作用。NO由神经元型、诱导型和内皮型三种不同亚型的一氧化氮合酶(NOS)合成。由于一氧化氮合酶亚型之间存在大量的代偿性相互作用，内源性一氧化氮在人体内的最终作用仍有待于充分阐明。在这里，我们已经成功地培育出了通过杂交单个NOS-/-小鼠而完全缺失所有三个NOS基因的小鼠。三联NOS-/-小鼠内毒素治疗前后均未见一氧化氮合酶的表达和活性。尽管三重NOS-/-小鼠存活并看起来正常，但与野生型小鼠相比，它们的存活率和受精率明显下降。此外，这些小鼠表现出明显的低渗性多尿、多饮和肾脏对抗利尿激素血管加压素的无反应，所有这些特征都符合肾源性尿崩症。在三重NOS-/-小鼠的肾脏中，血管加压素诱导的cAMP生成和膜水通道蛋白-2的表达减少，与肾小管小球病变形成有关。这些结果证明，一氧化氮合酶系统在维持体内平衡方面发挥着关键作用，尤其是在肾脏中。
Nitric oxide (NO) is produced in almost all tissues and organs, exerting a variety of biological actions under physiological and pathological conditions. NO is synthesized by three different isoforms of NO synthase (NOS), including neuronal, inducible, and endothelial NOSs. Because there are substantial compensatory interactions among the NOS isoforms, the ultimate roles of endogenous NO in our body still remain to be fully elucidated. Here, we have successfully developed mice in which all three NOS genes are completely deleted by crossbreeding singly NOS-/- mice. NOS expression and activities were totally absent in the triply NOS-/- mice before and after treatment with lipopolysaccharide. Although the triply NOS-/- mice were viable and appeared normal, their survival and fertility rates were markedly reduced as compared with the wild-type mice. Furthermore, these mice exhibited marked hypotonic polyuria, polydipsia, and renal unresponsiveness to an antidiuretic hormone, vasopressin, all of which are characteristics consistent with nephrogenic diabetes insipidus. In the kidney of the triply NOS-/- mice, vasopressin-induced cAMP production and membranous aquaporin-2 water channel expression were reduced associated with tubuloglomerular lesion formation. These results provide evidence that the NOS system plays a critical role in maintaining homeostasis, especially in the kidney.