Prevention of diabetic nephropathy in rats by prostaglandin E receptor EP1-selective antagonist.
Local production of prostaglandins (PGs) in the kidney is increased in clinical and experimental diabetic nephropathy, but the role of PGs in the pathogenesis and progression of diabetic nephropathy has remained unclear. It is here shown that an orally active antagonist selective for the PGE receptor EP1 subtype potently prevents the progression of nephropathy in streptozotocin-induced diabetic rats. The effects are shown by ameliorated renal and glomerular hypertrophy, decreased mesangial expansion, inhibited transcriptional activation of transforming growth factor-beta (TGF-beta) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-beta and fibronectin upregulation in mesangial cells cultured under high-glucose conditions. These data indicate that the PGE2-EP1 system plays a crucial role in the development of diabetic renal injury in rats. It is further shown that both the EP1 antagonist and aspirin, a nonselective PG synthase inhibitor, markedly attenuate mesangial expansion, whereas only the EP1 antagonist inhibits glomerular hypertrophy and proteinuria, which suggests that these changes are caused by different mechanisms. This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease.
Makino
Hisashi
H
Department of Medicine and Clinical Science, Department of Pharmacology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 806-8507, Japan.
Tanaka
Issei
I
Mukoyama
Masashi
M
Sugawara
Akira
A
Mori
Kiyoshi
K
Muro
Seiji
S
Suganami
Takayoshi
T
Yahata
Kensei
K
Ishibashi
Rieko
R
Ohuchida
Shuichi
S
Maruyama
Takayuki
T
Narumiya
Shuh
S
Nakao
Kazuwa
K
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D019898:Autocrine Communication; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000652:urine; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D005353:Fibronectins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology; D006984:Hypertrophy; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D002934:Cinnamates; D016861:Cyclooxygenase Inhibitors; D005353:Fibronectins; C411295:ONO 8713; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D016212:Transforming Growth Factor beta; D015232:Dinoprostone; D001241:Aspirin