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

Kidney Int. 2012 Jul;82(2):158-71. doi: 10.1038/ki.2012.115. Epub 2012 Apr 18.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Chemokine CCL5 / genetics
  • Chemokine CCL5 / metabolism
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism*
  • Disease Models, Animal
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Fibrosis
  • Folic Acid
  • Gene Expression Regulation
  • Heptanoates / pharmacology
  • Kidney Diseases / etiology
  • Kidney Diseases / genetics
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology
  • Kidney Diseases / prevention & control*
  • Kidney Tubules / drug effects
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • RNA, Messenger / metabolism
  • Receptors, Prostaglandin E, EP4 Subtype / agonists
  • Receptors, Prostaglandin E, EP4 Subtype / deficiency
  • Receptors, Prostaglandin E, EP4 Subtype / genetics
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism*
  • Signal Transduction
  • Time Factors
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Ureteral Obstruction / complications

Substances

  • CCN2 protein, mouse
  • Ccl2 protein, mouse
  • Ccl5 protein, mouse
  • Chemokine CCL2
  • Chemokine CCL5
  • Heptanoates
  • ONO4819
  • Ptger4 protein, mouse
  • RNA, Messenger
  • Receptors, Prostaglandin E, EP4 Subtype
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • Connective Tissue Growth Factor
  • Folic Acid
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Dinoprostone