Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

Abstract

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-␤ (TGF-␤) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-␤ 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.

Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice

“…Induction of diabetes Diabetes was induced in mice by daily intraperitoneal injection of streptozotocin (70 mg/kg body weight, for 4-7 days) (Sigma, St Louis, MO, USA) in citrate buffer until the blood glucose level was raised to >16.7 mmol/l [25]. Control mice received citrate buffer only.…”

“…Control mice received citrate buffer only. Blood glucose was measured in tail vein blood using the o-toluidine method (Sigma kit) [25] under non-fasted conditions. Blood pressure was measured every 4 weeks by the indirect tail-cuff method [23].…”

“…Cell culture Mesangial cells were established from glomeruli isolated from 10-week-old male Sprague-Dawley rats using a differential sieving method [25,26] and used at passages 7-10. Mesangial cells were identified by immunofluorescence techniques [26].…”

“…Northern blot analysis Total RNA was extracted from whole kidney and mesangial cells by the acid guanidinium-phenol-chloroform method and used for northern blot analysis as described previously [24,25]. In brief, 25 μg of total RNA was electrophoresed on 1.1% agarose gels containing 2.2 mol/l formaldehyde, and RNA was transferred onto nylon membrane filters.…”

Gallotannin ameliorates the development of streptozotocin‐induced diabetic nephropathy by preventing the activation of PARP

“…This indicates the development of diabetic nephropathy in these rats. An increase in plasma creatinine is considered a well known marker for the development of diabetic nephropathy (Makino et al, 2002;Breyer et al, 2005;Sharma et al, 2006). Creatinine is the breakdown product of creatine, which is mainly present in skeletal muscle.…”