Nephrogenic Diabetes Insipidus in Mice Lacking All Nitric Oxide Synthase Isoforms

Title: Nephrogenic Diabetes Insipidus in Mice Lacking All Nitric Oxide Synthase Isoforms
Authors: Morishita, Tsuyoshi; Tsutsui, MD, PhD, Masato; Shimokawa, Hiroaki; Sabanai, Ken; Tasaki, Hiromi; Suda, Osamu; Nakata, Sei; Tanimoto, Akihide; Wang, Ke-Yong; Ueta, Yoichi; Sasaguri, Yasuyuki; Nakashima, Yasuhide; Yanagihara, Nobuyuki
Publisher: Proceedings of the National Academy of Sciences of the United States of America
Date Published: July 26, 2005
Reference Number: 693
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.
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

Nitric oxide (NO) is an important messenger molecule within bodily cells that plays important roles in helping the body maintain homeostasis. NO synthases have three distinct isoforms. An isoform is any group of two or more different proteins produced by different genes and specific to different tissues in the body that have similar functions and amino acid sequences. Thus, the body has three distinct NO synthase forms, each formed by a different gene and each located in different bodily tissues. However, they are similar to each other both in form and function.

Because the NO synthase isoforms can compensate for each other should one be low in number, the ultimate role each plays in the human body is not clear. Morishita, et al., developed a line of mice that lack all three NO synthase genes, and therefore they have no NO in their bodies. Although these mice had a normal appearance, they had low survival and fertility rates. Further, these mice all developed NDI. When the researchers examined the kidneys of these mice, they found that the amount of cyclic adenosine monophosphate (cAMP) produced, in response to vasopressin stimulation, and the number of aquaporin-2 (AQP2) proteins were much lower than usual. In addition, lesions developed within the fine tubular structure of the kidneys.

Previous studies have indicated that NO both stimulates cAMP production and promotes AQP2 insertion into the membrane of collecting duct cells in the kidney. The work of Morishita, et al., confirmed the necessity of NO in these processes. In these mice, the functional abnormalities of NDI appeared before the occurrence of the structural abnormalities associated with NDI. Thus, the NDI in these mice appears more like inherited NDI than the acquired form of the disease.

The researchers conclude that NO plays a pivotal role in maintaining balance and stability in the body, especially in the kidneys.