Open AccessPrevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist
Author(s) -
Hisashi Makino,
Issei Tanaka,
Masashi Mukoyama,
Akira Sugawara,
Kiyoshi Mori,
Seiji Muro,
Takayoshi Suganami,
Kensei Yahata,
Rieko Ishibashi,
Shuichi Ohuchida,
Takayuki Maruyama,
Shuh Narumiya,
Kazuwa Nakao
Publication year - 2002
Publication title -
journal of the american society of nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.451
H-Index - 279
eISSN - 1533-3450
pISSN - 1046-6673
DOI - 10.1097/01.asn.0000019782.37851.bf
Subject(s) - diabetic nephropathy , medicine , endocrinology , renal hypertrophy , antagonist , receptor antagonist , downregulation and upregulation , kidney , receptor , chemistry , biochemistry , gene
. 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-β (TGF-β) and fibronectin, and complete suppression of proteinuria. In vitro , this agent completely inhibits TGF-β 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.