Chronic kidney disease (CKD) affects approximately 10% of the adult population in developed countries. Kidney fibrosis plays a pivotal role in the development and progression of CKD as well as in kidney transplant failure. Fibrosis results in the loss of organ architecture and function. It is the most damaging process in CKD. The COX-2/prostaglandin system plays a dominant role in the progression of kidney 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 kidney hemodynamics as well as water and salt balance. PGE2 exerts its biological activity by activating prostaglandin receptor, known as EP1-EP4 receptors. Several studies have demonstrated an important role for the EP1-EP4 receptors in kidney injury.

Butaprost (HY-100448A) is a selective EP2 receptor agonist with a K_i of 2.4 μM for murine EP2 receptor. It is less activity against murine EP1, EP3 and EP4 receptors. Moreover, It attenuates fibrosis by hampering TGF-β/Smad signaling. Butaprost mitigates TGF‐β‐induced epithelial-mesenchymal transition (EMT). It also reduces TGF-β-induced fibronectin (FN) expression, Smad2 phosphorylation and EMT in Madin-Darby Canine Kidney (MDCK) cells. In addition, Butaprost attenuates the development of fibrosis in mice that underwent unilateral ureteral obstruction (UUO) surgery, as illustrated by a reduction in the gene and protein expression of α-smooth muscle actin (α-SMA), fibronectin and collagen 1A1.

In conclusion, stimulation of the EP2 receptor can effectively mitigate kidney fibrogenesis in various fibrosis models, such as in MDCK cells, UUO mice, and human precision‐cut kidney slices (PCKS).