Role of Prostaglandin E Receptor EP 1 Subtype in the Development of Renal Injury in Genetically Hypertensive Rats

Abstract

One of the major causes of end-stage renal diseases is hypertensive renal disease, in which enhanced renal prostaglandin (PG) E 2 production has been shown. PGE 2 , a major arachidonic acid metabolite produced in the kidney, acts on 4 receptor subtypes, EP 1 through EP 4 , but the pathophysiological importance of the PGE 2 /EP subtypes in the development of hypertensive renal injury remains to be elucidated. In this study, we investigated whether an orally active EP 1 -selective antagonist (EP 1 A) 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 EP 1 A or vehicle for 5 weeks. After the treatment period, vehicle-treated SHRSP showed prominent proliferative lesions in arterioles, characterized by decreased α-smooth muscle actin expression in multilayered vascular smooth muscle cells. Upregulation of transforming growth factor-β expression and tubulointerstitial fibrosis were also observed in vehicle-treated SHRSP. All these changes were dramatically attenuated in EP 1 A-treated SHRSP. Moreover, EP 1 A 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 PGE 2 /EP 1 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 EP 1 for the treatment of hypertensive renal disease.