The intrinsic prostaglandin E2–EP4 system of the renal tubular epithelium limits the development of tubulointerstitial fibrosis in mice

Abstract

Inflammatory responses in the kidney lead to tubulointerstitial fibrosis, a common feature of chronic kidney diseases. Here we examined the role of prostaglandin E(2) (PGE(2)) in the development of tubulointerstitial fibrosis. In the kidneys of wild-type mice, unilateral ureteral obstruction leads to progressive tubulointerstitial fibrosis with macrophage infiltration and myofibroblast proliferation. This was accompanied by an upregulation of COX-2 and PGE(2) receptor subtype EP(4) mRNAs. In the kidneys of EP(4) gene knockout mice, however, obstruction-induced histological alterations were significantly augmented. In contrast, an EP(4)-specific agonist significantly attenuated these alterations in the kidneys of wild-type mice. The mRNAs for macrophage chemokines and profibrotic growth factors were upregulated in the kidneys of wild-type mice after ureteral obstruction. This was significantly augmented in the kidneys of EP(4)-knockout mice and suppressed by the EP(4) agonist but only in the kidneys of wild-type mice. Notably, COX-2 and MCP-1 proteins, as well as EP(4) mRNA, were localized in renal tubular epithelial cells after ureteral obstruction. In cultured renal fibroblasts, another EP(4)-specific agonist significantly inhibited PDGF-induced proliferation and profibrotic connective tissue growth factor production. Hence, an endogenous PGE(2)-EP(4) system in the tubular epithelium limits the development of tubulointerstitial fibrosis by suppressing inflammatory responses.

Prostaglandin E2 regulates murine hematopoietic stem/progenitor cells directly via EP4 receptor and indirectly through mesenchymal progenitor cells

“…Indeed, it has recently been reported that PGE 2 /EP4 pathway has an antifibrosis effect in kidney interstitial cells. 43 In this study, we found that PGE 2 indirectly induced HSPC proliferation through the activation of MPCs. A more comprehensive understanding of these indirect effects of PGE 2 may facilitate the expansion of HSPCs for use in regenerative medicine.…”

Prostaglandin E2 Inhibits α-Smooth Muscle Actin Transcription during Myofibroblast Differentiation via Distinct Mechanisms of Modulation of Serum Response Factor and Myocardin-related Transcription Factor-A

“…Culturing lung fibroblasts on stiff matrix, which activates adhesive signaling and is sufficient to trigger myofibroblast differentiation, has likewise been reported to down-regulate PGE 2 synthetic capacity (48). Deficient endogenous PGE 2 synthesis or actions promotes fibrogenesis, as evidenced by studies employing pharmacological interruption of PGE 2 synthesis (46, 49) and deletion of cAMP-coupled EP2 (50) and EP4 receptors (51). Taken together, this body of literature suggests that, rather than merely being of interest as an exogenously added substance, the suppressive actions of endogenous PGE 2 are so fundamental that tissue fibrogenesis can only occur when this potent antifibrotic brake is down-regulated.…”

An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

“…8,12) Unilateral ureteral obstruction has been used to induce kidney fibrosis, and EP4 agonist mitigated interstitial fibrosis in this mouse model of chronic kidney disease. 21) These studies have indicated EP4 agonists have antifibrotic and organ protective effects. Pressure overload to the heart can cause acute myocardial injury and edema in acute phase, which is followed by the gradual development of fibrosis.…”