Delayed blockage of prostaglandin EP4 receptors can reduce dedifferentiation, epithelial-to-mesenchymal transition and fibrosis following acute kidney injury.

Dedifferentiation of tubular epithelial cells is involved in both regeneration and fibrosis following acute kidney injury (AKI). Prostaglandin E₂ receptor 4 (EP₄ ) antagonist can inhibit the dedifferentiation of renal tubular cells. The present study investigated whether the time of blockage of EP₄ receptors, using grapiprant, could affect the tubular regeneration or interstitial fibrosis in AKI. Cisplatin was used to induce AKI in 72 C57BL/6 adult female mice. Animals were assigned to four groups; control, cisplatin-treated, cisplatin-treated with early grapiprant intervention and cisplatin-treated with late grapiprant intervention. AKI was assessed by kidney function tests and histopathology. Fibrosis was evaluated by Masson's trichrome and alpha smooth muscle actin (α-SMA) expression. Markers of dedifferentiation, CD133, and epithelial to mesenchymal transition (EMT), vimentin were assessed. Early intervention with grapiprant significantly ameliorated AKI more efficiently than late intervention. However, even late intervention was useful in reducing the overall fibrosis as demonstrated by Masson's trichrome and α-SMA expression. In both grapiprant-treated groups, a parallel reduction of dedifferentiation (CD133) and EMT (vimentin) was evident. It seems that the progressive fibrotic changes that follow AKI could still be reduced possibly by targeting dedifferentiation and/or EMT.