Renoprotective effects of the novel prostaglandin EP4 receptor-selective antagonist ASP7657 in 5/6 nephrectomized chronic kidney disease rats
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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.
KeywordsProstaglandin EP4 receptor antagonist Hyperfiltration Renin release Chronic kidney disease
The authors thank Drs. Akiyoshi Shimaya, Yuichi Tomura, and Atsuo Tahara (Astellas Pharma Inc.) for their valuable comments and continuing encouragement.
KM, HY, EN, KW, and TU conceived and designed the research. KM, HY, and TU performed experiments and analyzed the data. EN contributed to the synthesis of ASP7657. KM and KW wrote the manuscript. All authors read and approved the manuscript.
Compliance with ethical standards
Animal studies were approved by the Institutional Animal Care and Use Committee of Astellas Pharma Inc., Tsukuba Research Center, which is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International.
Conflict of interest
The authors have no conflict of interest other than being employees of Astellas Pharma Inc.
- Kondo M, Tahara A, Hayashi K, Abe M, Inami H, Ishikawa T, Ito H, Tomura Y (2014) Renoprotective effects of novel interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 through anti-inflammatory action in 5/6 nephrectomized rats. Naunyn Schmiedeberg's Arch Pharmacol 387:909–919CrossRefGoogle Scholar
- Lambers Heerspink HJ, de Zeeuw D (2013) Novel drugs and intervention strategies for the treatment of chronic kidney disease. Br J Clin Pharmacol 76:536–550Google Scholar
- Macconi D (2010) Targeting the renin angiotensin system for remission/regression of chronic kidney disease. Histol Histopathol 25:655–668Google Scholar
- Ravera M, Re M, Deferrari L, Vettoretti S, Deferrari G (2006) Importance of blood pressure control in chronic kidney disease. J Am Soc Nephrol 17:S98–S103Google Scholar
- Sugimoto H, Shikata K, Matsuda M, Kushiro M, Hayashi Y, Hiragushi K, Wada J, Makino H (1998) Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy. Diabetologia 41:1426–1434CrossRefGoogle Scholar
- Tahara A, Kurosaki E, Yokono M, Yamajuku D, Kihara R, Hayashizaki Y, Takasu T, Imamura M, Li Q, Tomiyama H, Kobayashi Y, Noda A, Sasamata M, Shibasaki M (2014) Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats. J Pharm Pharmacol 66:975–987CrossRefGoogle Scholar