EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease
2017
The therapeutic targeting of
prostanoidsubtype 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
albuminuriato 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-s1 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 systemblockade. EP4 inhibition may represent a viable
repurposingopportunity for the treatment of CKD.
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