Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist
- 1 July 2002
- journal article
- research article
- Published by Wolters Kluwer Health in Journal of the American Society of Nephrology
- Vol. 13 (7) , 1757-1765
- https://doi.org/10.1097/01.asn.0000019782.37851.bf
Abstract
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.Keywords
This publication has 13 references indexed in Scilit:
- Nephropathy in Patients with Type 2 Diabetes MellitusNew England Journal of Medicine, 1999
- Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38BMJ, 1998
- Reversal of Lesions of Diabetic Nephropathy after Pancreas TransplantationNew England Journal of Medicine, 1998
- ROLE FOR LOCAL PROSTAGLANDIN AND THROMBOXANE PRODUCTION IN THE REGULATION OF GLOMERULAR-FILTRATION RATE IN THE RAT WITH STREPTOZOCIN-INDUCED DIABETES1989
- EFFECT OF ASPIRIN ON EXPERIMENTAL DIABETIC NEPHROPATHY1987
- Multiple sites of alternative splicing of the rat fibronectin gene transcript.The EMBO Journal, 1987
- Effects of indomethacin on kidney function in Type 1 (insulin-dependent) diabetic patients with nephropathyDiabetologia, 1987
- Increased prostaglandin production by glomeruli isolated from rats with streptozotocin-induced diabetes mellitus.Journal of Clinical Investigation, 1985
- Structural-functional relationships in diabetic nephropathy.Journal of Clinical Investigation, 1984
- Streptozotocin-Induced Pancreatic Insulitis: New Model of Diabetes MellitusScience, 1976