ono-8713 and Proteinuria

One of the major causes of end-stage renal diseases is hypertensive renal disease, in which enhanced renal prostaglandin (PG) E2 production has been shown. PGE2, a major arachidonic acid metabolite produced in the kidney, acts on 4 receptor subtypes, EP1 through EP4, but the pathophysiological importance of the PGE2/EP subtypes in the development of hypertensive renal injury remains to be elucidated. In this study, we investigated whether an orally active EP1-selective antagonist (EP1A) prevents the progression of renal damage in stroke-prone spontaneously hypertensive rats (SHRSP), a model of human malignant hypertension. Ten-week-old SHRSP, with established hypertension but with minimal renal damage, were given EP1A or vehicle for 5 weeks. After the treatment period, vehicle-treated SHRSP showed prominent proliferative lesions in arterioles, characterized by decreased alpha-smooth muscle actin expression in multilayered vascular smooth muscle cells. Upregulation of transforming growth factor-beta expression and tubulointerstitial fibrosis were also observed in vehicle-treated SHRSP. All these changes were dramatically attenuated in EP1A-treated SHRSP. Moreover, EP1A treatment significantly inhibited both increase in urinary protein excretion and decrease in creatinine clearance but had little effect on systemic blood pressure. These findings indicate that the PGE2/EP1 signaling pathway plays a crucial role in the development of renal injury in SHRSP. This study opens a novel therapeutic potential of selective blockade of EP1 for the treatment of hypertensive renal disease.

Topics: Animals; Blood Pressure; Cells, Cultured; Cinnamates; Cyclooxygenase 1; Fibrosis; Glomerular Mesangium; Hypertension; Isoenzymes; Kidney; Kidney Diseases; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype

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.

Topics: Animals; Aspirin; Autocrine Communication; Cells, Cultured; Cinnamates; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dinoprostone; Disease Progression; Fibronectins; Glomerular Mesangium; Hypertrophy; Kidney; Kidney Glomerulus; Proteinuria; Rats; Rats, Wistar; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Tissue Distribution; Transforming Growth Factor beta; Up-Regulation