ono4819 and Fibrosis

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.

Topics: Animals; Cell Proliferation; Cells, Cultured; Chemokine CCL2; Chemokine CCL5; Connective Tissue Growth Factor; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Epithelial Cells; Fibrosis; Folic Acid; Gene Expression Regulation; Heptanoates; Kidney Diseases; Kidney Tubules; Macrophages; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Myofibroblasts; Receptors, Prostaglandin E, EP4 Subtype; RNA, Messenger; Signal Transduction; Time Factors; Transforming Growth Factor beta1; Ureteral Obstruction