Prostaglandins (PGs) are important
lipid mediators of numerous physiologic and pathophysiologic processes in the kidney.
PGE2, the most abundant renal PG, plays a major role in renal physiology, including
renin release and glomerular hemodynamics. We investigated the renoprotective properties of the novel
PGE2 EP4 receptor-selective antagonist
ASP7657 in 5/6 nephrectomized rats, a
chronic kidney disease (CKD) model. Eight weeks of repeated administration of
ASP7657 (0.001-0.1 mg/kg) dose-dependently and significantly reduced urinary
protein excretion and attenuated the development of glomerulosclerosis and tubulointerstitial damage, including
fibrosis and inflammatory cell infiltration, without affecting blood pressure. Additionally,
ASP7657 tended to have beneficial effects on renal function, as indicated by the decrease in plasma
creatinine and blood
urea nitrogen levels and attenuation of the decline in
creatinine clearance (Ccr). The
angiotensin II receptor blocker losartan (10 mg/kg) also showed these renoprotective effects while significantly reducing blood pressure.
ASP7657 dose-dependently and significantly reduced the EP4 receptor agonist-induced increase in plasma
renin activity, as assessed by
angiotensin I release in normal rats. Additionally,
ASP7657 attenuated hyperfiltration assessed by Ccr without changing the renal blood flow or blood pressure in diabetic rats. These results suggest that
ASP7657 suppresses the progression of
chronic renal failure by modulating
renin release and improving renal hemodynamics, and may therefore be a promising therapeutic option for inhibiting the progression of CKD.