title: 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.
authors.affiliation: Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakagawa
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Yuhki
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kawabe
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujino
authors.forename: Osamu
authors.initials: O
authors.lastname: Takahata
authors.forename: Maki
authors.initials: M
authors.lastname: Kabara
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Abe
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Kojima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kashiwagi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hasebe
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ushikubi
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D005492:Folic Acid; D005786:Gene Expression Regulation; D006537:Heptanoates / Q000494:pharmacology; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: C526318:CCN2 protein, mouse; C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D006537:Heptanoates; C487764:ONO4819; C545651:Ptger4 protein, mouse; D012333:RNA, Messenger; D058309:Receptors, Prostaglandin E, EP4 Subtype; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D005492:Folic Acid; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone