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

Abstract

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.

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

“…To explore the potential role of EP receptors in the procedure of AKI-to-CKD transition, we first screened the expressions of the four G-protein-coupled receptors EP receptors in mouse kidney tissues at 2 and 14 days after IRI though single nucleus RNA sequencing (snRNA-Seq) acquired from GEO datasets (GSE139107) (Figure 1A). Although both EP3 and EP4 were highly expressed in the kidney (Figure 1B), previous studies have confirmed that EP3 was not significantly altered in the kidney of AKI mice (Abouelkheir et al, 2021). Therefore, we focused on EP4 in subsequent experiments.…”

Prostaglandin E2 receptors as therapeutic targets in renal fibrosis

“…The beneficial effect of EP4 receptor blockade was also seen in a mouse model of cisplatin-induced kidney damage. In these mice, treatment with the EP4 antagonist grapiprant, a nonsteroidal anti-inflammatory drug widely used in veterinary medicine [ 79 ], markedly reduced collagen deposition and α-smooth muscle actin expression associated with cisplatin exposure [ 80 ]. Taken together, the EP4 receptor has been the greatest focus of research to develop new renal fibrosis therapies.…”

Cellular senescence and acute kidney injury

“…EMT transforms epithelial cells into myofibroblasts; these myofibroblasts proliferate and produce a fibrotic matrix [ 58 ]. A prostaglandin E-2 receptor 4 (EP4) antagonist can inhibit the de-differentiation of renal tubular cells, which targets EMT [ 59 ]. Conversely, cells in acute senescence can undergo cellular reprogramming to de-differentiate, proliferate, and differentiate to achieve tissue regeneration and repair in AKI.…”