EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease

Sci Rep. 2017 Jun 13;7(1):3442. doi: 10.1038/s41598-017-03237-3.


The therapeutic targeting of prostanoid subtype receptors may slow the development of chronic kidney disease (CKD) through mechanisms that are distinct from those of upstream COX inhibition. Here, employing multiple experimental models of CKD, we studied the effects of inhibition of the EP4 receptor, one of four receptor subtypes for the prostanoid prostaglandin E2. In streptozotocin-diabetic endothelial nitric oxide synthase knockout mice, EP4 inhibition attenuated the development of albuminuria, whereas the COX inhibitor indomethacin did not. In Type 2 diabetic db/db mice, EP4 inhibition lowered albuminuria to a level comparable with that of the ACE inhibitor captopril. However, unlike captopril, EP4 inhibition had no effect on blood pressure or hyperfiltration although it did attenuate mesangial matrix accumulation. Indicating a glucose-independent mechanism of action, EP4 inhibition also attenuated proteinuria development and glomerular scarring in non-diabetic rats subjected to surgical renal mass ablation. Finally, in vitro, EP4 inhibition prevented transforming growth factor-ß1 induced dedifferentiation of glomerular podocytes. In rodent models of diabetic and non-diabetic CKD, EP4 inhibition attenuated renal injury through mechanisms that were distinct from either broadspectrum COX inhibition or "standard of care" renin angiotensin system blockade. EP4 inhibition may represent a viable repurposing opportunity for the treatment of CKD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Diabetic Nephropathies / drug therapy*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Naphthalenes / pharmacology*
  • Naphthalenes / therapeutic use
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism
  • Phenylbutyrates / pharmacology*
  • Phenylbutyrates / therapeutic use
  • Podocytes / drug effects
  • Podocytes / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin E, EP4 Subtype / antagonists & inhibitors*
  • Renal Insufficiency, Chronic / drug therapy*
  • Transforming Growth Factor beta / metabolism


  • 4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid
  • Naphthalenes
  • Phenylbutyrates
  • Receptors, Prostaglandin E, EP4 Subtype
  • Transforming Growth Factor beta
  • Nitric Oxide Synthase Type III