Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury by inhibiting COX-2-mediated PGE2 production

Punithavathi V. Ranganathan, Calpurnia Jayakumar, Riyaz Mohamed, Zheng Dong, Ganesan Ramesh

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Netrin-1 regulates inflammation but the mechanism by which this occurs is unknown. Here we explore the role of netrin-1 in regulating the production of the prostanoid metabolite PGE2 from neutrophils in in vitro and in vivo disease models. Ischemia reperfusion in wild-type and RAG-1 knockout mice induced severe kidney injury that was associated with a large increase in neutrophil infiltration and COX-2 expression in the infiltrating leukocytes. Administration of netrin-1 suppressed COX-2 expression, PGE2 and thromboxane production, and neutrophil infiltration into the kidney. This was associated with reduced apoptosis, inflammatory cytokine and chemokine expression, and improved kidney function. Treatment with the PGE2 receptor EP4 agonist enhanced neutrophil infiltration and renal injury, which was not inhibited by netrin-1. Consistent with in vivo data, both LPS-and IFNγ-induced inflammatory cytokine production in macrophages and IL-17-induced IFNγ production in neutrophils were suppressed by netrin-1 in vitro by suppression of COX-2 expression. Moreover, netrin-1 regulates COX-2 expression at the transcriptional level through the regulation of NFκB activation. Thus, netrin-1 regulates the inflammatory response of neutrophils and macrophages through suppression of COX-2-mediated PGE2 production. This could be a potential drug for treating many inflammatory immune disorders.

Original languageEnglish (US)
Pages (from-to)1087-1098
Number of pages12
JournalKidney International
Volume83
Issue number6
DOIs
StatePublished - Jan 1 2013

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Dinoprostone
Acute Kidney Injury
Neutrophils
Macrophages
Neutrophil Infiltration
Kidney
Prostaglandin E Receptors
Cytokines
Interleukin-17
Thromboxanes
Immune System Diseases
Wounds and Injuries
netrin-1
Chemokines
Knockout Mice
Reperfusion
Prostaglandins
Leukocytes
Ischemia
Inflammation

Keywords

  • Cyclooxygenase
  • Inflammation
  • Netrin-1
  • PGE2

ASJC Scopus subject areas

  • Nephrology

Cite this

Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury by inhibiting COX-2-mediated PGE2 production. / Ranganathan, Punithavathi V.; Jayakumar, Calpurnia; Mohamed, Riyaz; Dong, Zheng; Ramesh, Ganesan.

In: Kidney International, Vol. 83, No. 6, 01.01.2013, p. 1087-1098.

Research output: Contribution to journalArticle

Ranganathan, Punithavathi V. ; Jayakumar, Calpurnia ; Mohamed, Riyaz ; Dong, Zheng ; Ramesh, Ganesan. / Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury by inhibiting COX-2-mediated PGE2 production. In: Kidney International. 2013 ; Vol. 83, No. 6. pp. 1087-1098.
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