Chronic kidney disease (CKD) affects approximately 10% of the adult population in developed countries. Renal fibrosis plays a pivotal role in the development and progression of CKD as well as in renal transplant failure. Fibrosis results in the loss of organ architecture and function. It is the most damaging process in CKD. the COX-2/prostaglandin (PG) system plays a dominant role in the progression of renal injury. COX enzymes catalyze the conversion of arachidonic acid into prostaglandins, including prostaglandin E2 (PGE2), which is an important mediator of numerous physiological processes in the kidney, including renal hemodynamics as well as water and salt balance. PGE2 exerts its biological activity by activating several G protein-coupled prostanoid receptors, known as EP1-EP4. Several studies have demonstrated an important role for the EP1-EP4 receptors in renal injury. Butaprost is a selective EP2 agonist.
Butaprost is a selective EP2 agonist with a Ki of 2.4 μM for murine EP2 receptor. It is less activity against murine EP1, EP3 and EP4 receptors. Moreover, Butaprost mitigates TGF‐β‐induced epithelial-mesenchymal transition (EMT). It also reduces TGF-β-induced fibronectin (FN) expression, Smad2 phosphorylation and epithelial-mesenchymal transition in Madin-Darby Canine Kidney (MDCK) cells. In addition, Butaprost attenuates the development of fibrosis in mice that underwent unilateral ureteral obstruction surgery, as illustrated by a reduction in the gene and protein expression of α-smooth muscle actin, fibronectin and collagen 1A1.
In conclusion, stimulation of the EP2 receptor can effectively mitigate renal fibrogenesis in various fibrosis models. Butaprost successfully mitigates fibrogenesis in MDCK cells, UUO mice, and human PCKS. It also attenuates fibrosis by hampering TGF-β/Smad2 signaling.