Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms.

Abstract

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.

• Authors: Tsuyoshi Morishita, Masato Tsutsui, Hiroaki Shimokawa, Ken Sabanai, Hiromi Tasaki, Osamu Suda, Sei Nakata, Akihide Tanimoto, Ke-Yong Wang, Yoichi Ueta, Yasuyuki Sasaguri, Yasuhide Nakashima, Nobuyuki Yanagihara
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 30 Pg. 10616-21 (Jul 26 2005) ISSN: 0027-8424 [Print] United States
• PMID: 16024729 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aqp2 protein, mouse
• Aquaporin 2
• Isoenzymes
• Lipopolysaccharides
• Vasopressins
• Cyclic AMP
• Nitric Oxide Synthase

Topics

• Analysis of Variance
• Animals
• Aquaporin 2 (metabolism)
• Blood Chemical Analysis
• Blotting, Western
• Crosses, Genetic
• Cyclic AMP (metabolism)
• Diabetes Insipidus, Nephrogenic (enzymology)
• Isoenzymes (deficiency)
• Kidney (drug effects, metabolism)
• Lipopolysaccharides
• Mice
• Mice, Knockout
• Nitric Oxide Synthase (deficiency)
• Osmolar Concentration
• Survival Analysis
• Vasopressins (pharmacology, urine)