Published Online
on October 14, 2002

A more recent version of this article appeared on October 29, 2002

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Submitted on May 14, 2002
Revised on August 6, 2002
Accepted on August 6, 2002

Prostacyclin-Deficient Mice Develop Ischemic Renal Disorders, Including Nephrosclerosis and Renal Infarction

Chieko Yokoyama PhD, Tomoko Yabuki PhD, Manabu Shimonishi PhD, Masayuki Wada MSc, Toshihisa Hatae PhD, Susumu Ohkawara PhD, Junji Takeda MD, PhD, Taroh Kinoshita PhD, Masaru Okabe PhD, and Tadashi Tanabe PhD^*

From the Department of Pharmacology, National Cardiovascular Center Research Institute (C.Y., T.Y., M.S., M.W., T.H., S.O., T.T.), Division of Microcirculatory Kinetics (M.W., T.T.), and Department of Social and Environmental Medicine (J.T.), Graduate School of Medicine, Research Institute for Microbial Diseases (T.K.), and Genome Information Research Center (M.O.), Osaka University, Suita, Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: tanabe{at}kiko.go.jp.

Background—Prostacyclin (PGI₂) is a short-lived endogenous inhibitor of platelet aggregation and a potent vasodilator and regulator of the growth of vascular smooth muscle cells. To study the role of PGI₂ in the vascular system in vivo, PGI₂-deficient (PGID) mice were established by genetic disruption of the PGI₂ synthase gene.

Methods and Results—PGI₂ synthase-null mice were generated by replacing the exons of PGI₂ synthase gene that encodes for the catalytic site of the enzyme with a neomycin resistance gene. In these mice, PGI₂ levels in the plasma, kidneys, and lungs were reduced, whereas thromboxane and prostaglandin E₂ levels became elevated. Blood pressure and the amounts of urea nitrogen and creatinine in plasma of the PGID mice were significantly higher than those of wild-type mice (P<0.05). They developed progressive morphological abnormalities in the kidneys, accompanied by atrophy, surface irregularity, fibrosis, cyst, arterial sclerosis, and hypertrophy of vessel walls. Thickening of the thoracic aortic media and adventitia were observed in aged PGID mice. Importantly, these phenotypes have not been reported in PGI₂ receptor-deficient mice.

Conclusions—PGI₂ deficiency resulted in the development of vascular disorders with the thickening of vascular walls and interstitial fibrosis, especially in mouse kidneys. The findings demonstrated in vivo that PGI₂ is important in the homeostasis of blood vessels. Our established PGID mice are useful for studies on the initiation and development of vascular diseases, such as ischemic renal disorders with arterial sclerosis and infarction, and also for studies on the novel signaling pathway of PGI₂.

Key words: prostaglandins • thromboxane • kidney • arteriosclerosis • hypertension

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