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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Proliferation
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Cells, Cultured
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Chemokine CCL2 / genetics
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Chemokine CCL2 / metabolism
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Chemokine CCL5 / genetics
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Chemokine CCL5 / metabolism
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Connective Tissue Growth Factor / genetics
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Connective Tissue Growth Factor / metabolism
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Dinoprostone / metabolism*
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Disease Models, Animal
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Fibrosis
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Folic Acid
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Gene Expression Regulation
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Heptanoates / pharmacology
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Kidney Diseases / etiology
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Kidney Diseases / genetics
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Kidney Diseases / metabolism
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Kidney Diseases / pathology
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Kidney Diseases / prevention & control*
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Kidney Tubules / drug effects
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Kidney Tubules / metabolism*
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Kidney Tubules / pathology
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Macrophages / metabolism
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Macrophages / pathology
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Knockout
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Myofibroblasts / metabolism
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Myofibroblasts / pathology
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RNA, Messenger / metabolism
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Receptors, Prostaglandin E, EP4 Subtype / agonists
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Receptors, Prostaglandin E, EP4 Subtype / deficiency
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Receptors, Prostaglandin E, EP4 Subtype / genetics
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Receptors, Prostaglandin E, EP4 Subtype / metabolism*
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Signal Transduction
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Time Factors
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism
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Ureteral Obstruction / complications
Substances
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CCN2 protein, mouse
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Ccl2 protein, mouse
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Ccl5 protein, mouse
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Chemokine CCL2
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Chemokine CCL5
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Heptanoates
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ONO4819
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Ptger4 protein, mouse
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RNA, Messenger
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Receptors, Prostaglandin E, EP4 Subtype
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Tgfb1 protein, mouse
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Transforming Growth Factor beta1
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Connective Tissue Growth Factor
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Folic Acid
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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Dinoprostone