Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms.
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.
Morishita
Tsuyoshi
T
Second Department of Internal Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
Tsutsui
Masato
M
Shimokawa
Hiroaki
H
Sabanai
Ken
K
Tasaki
Hiromi
H
Suda
Osamu
O
Nakata
Sei
S
Tanimoto
Akihide
A
Wang
Ke-Yong
KY
Ueta
Yoichi
Y
Sasaguri
Yasuyuki
Y
Nakashima
Yasuhide
Y
Yanagihara
Nobuyuki
N
D000704:Analysis of Variance; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D001774:Blood Chemical Analysis; D015153:Blotting, Western; D003433:Crosses, Genetic; D000242:Cyclic AMP / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000201:enzymology*; D007527:Isoenzymes / Q000172:deficiency; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000172:deficiency*; D009994:Osmolar Concentration; D016019:Survival Analysis; D014667:Vasopressins / Q000494:pharmacology / Q000652:urine
C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D007527:Isoenzymes; D008070:Lipopolysaccharides; D014667:Vasopressins; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase