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(Hypertension. 2003;42:1183.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Role of Prostaglandin E Receptor EP₁ Subtype in the Development of Renal Injury in Genetically Hypertensive Rats

Takayoshi Suganami; Kiyoshi Mori; Issei Tanaka; Masashi Mukoyama; Akira Sugawara; Hisashi Makino; Seiji Muro; Kensei Yahata; Shuichi Ohuchida; Takayuki Maruyama; Shuh Narumiya; Kazuwa Nakao

From the Department of Medicine and Clinical Science (T.S., K.M., I.T., M.M., A.S., H.M., S.M., K.Y., K.N.) and the Department of Pharmacology (S.N.), Kyoto University Graduate School of Medicine, Kyoto Japan; and Discovery Research Laboratories (S.O., T.M.), Minase Research Institute, Ono Pharmaceutical Co, Ltd, Osaka, Japan.

Correspondence to Issei Tanaka, MD, PhD, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail isseitnk{at}cam.hi-ho.ne.jp

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 -smooth muscle actin expression in multilayered vascular smooth muscle cells. Upregulation of transforming growth factor-ß 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.

Key Words: rats, stroke-prone SHR • prostaglandins • arachidonic acids • transforming growth factors • kidney • proteinuria

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