Chronic administration of EP4-selective agonist exacerbates albuminuria and fibrosis of the kidney in streptozotocin-induced diabetic mice through IL-6

Riyaz Mohamed, Calpurnia Jayakumar, Ganesan Ramesh

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Diabetic nephropathy is currently the most common cause of end-stage renal disease in the western world. Exacerbated inflammation of the kidney is known to contribute acceleration of nephropathy. Despite increased COX-2-mediated production of prostanoid metabolite PGE2, knowledge on its involvement in the progression of diabetic kidney disease is not complete. Here, we show the cross talk of the PGE2-EP4 pathways and IL-6 in inducing albuminuria and fibrosis in an animal model of type 1 diabetes. Hyperglycemia causes enhanced COX-2 expression and PGE2 production. Administration of PGE2 receptor EP4-selective agonist ONO-AE1-329 for 12 weeks exacerbated fibrosis and albuminuria. Diabetes-induced expression of inflammatory cytokines TNFα and TGFβ1 was enhanced in EP4 agonist-treated mice kidney. In addition, urinary excretion of cytokines (TNFα and IL-6) and chemokines (MCP-1 and IP-10) were significantly more in EP4-treated mice than vehicle-treated diabetes. Diabetes-induced collagen I and CTGF expression were also significantly higher in EP4-treated mice. However, EP4 agonist did not alter macrophage infiltration but increased cytokine and chemokine production in RAW264.7 cells. Interestingly, EP4-induced IL-6 expression in the kidney was localized in proximal and distal tubular epithelial cells. To confirm further whether EP4 agonist increases fibrosis and albuminuria through an increase in IL-6 expression, IL-6-knockout mice were administered with EP4 agonist. IL-6-knockout mice were resistant to EP4-induced exacerbation of albuminuria and diabetes and EP4-induced fibrosis. Our data suggest that EP4 agonist through IL-6 induces glomerulosclerosis and interstitial fibrosis, and IL-6 represents a new factor in the EP4 pathway.

Original languageEnglish (US)
Pages (from-to)933-945
Number of pages13
JournalLaboratory Investigation
Volume93
Issue number8
DOIs
StatePublished - Aug 2013

Keywords

  • Albuminuria
  • Chronic kidney disease
  • EP4 agonist
  • Inflammation
  • Nephropathy
  • Prostaglandin E2

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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