Prostacyclin-deficient mice develop ischemic renal disorders, including nephrosclerosis and renal infarction.
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.


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.
Yokoyama
Chieko
C
Department of Pharmacology, National Cardiovascular Center Research Institute, Osaka University, Suita, Osaka, Japan.
Yabuki
Tomoko
T
Shimonishi
Manabu
M
Wada
Masayuki
M
Hatae
Toshihisa
T
Ohkawara
Susumu
S
Takeda
Junji
J
Kinoshita
Taroh
T
Okabe
Masaru
M
Tanabe
Tadashi
T
D000367:Age Factors; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001794:Blood Pressure / Q000235:genetics; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D011464:Epoprostenol / Q000172:deficiency* / Q000235:genetics; D006339:Heart Rate / Q000235:genetics; D007238:Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009400:Nephrosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011453:Prostaglandins / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism
D011453:Prostaglandins; D013929:Thromboxane B2; D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine; D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D015232:Dinoprostone