HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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.
AuthorsPunithavathi V Ranganathan, Calpurnia Jayakumar, Riyaz Mohamed, Zheng Dong, Ganesan Ramesh
JournalKidney international (Kidney Int) Vol. 83 Issue 6 Pg. 1087-98 (Jun 2013) ISSN: 1523-1755 [Electronic] United States
PMID23447066 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Anti-Inflammatory Agents
  • Cytokines
  • Homeodomain Proteins
  • Inflammation Mediators
  • NF-kappa B
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • RAG-1 protein
  • Netrin-1
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Dinoprostone
Topics
  • Acute Kidney Injury (enzymology, genetics, immunology, pathology, prevention & control)
  • Animals
  • Anti-Inflammatory Agents (pharmacology)
  • Cell Line
  • Cyclooxygenase 2 (genetics, metabolism)
  • Cytokines (metabolism)
  • Dinoprostone (metabolism)
  • Disease Models, Animal
  • Down-Regulation
  • Homeodomain Proteins (genetics, metabolism)
  • Inflammation (enzymology, genetics, immunology, pathology, prevention & control)
  • Inflammation Mediators (metabolism)
  • Kidney (drug effects, enzymology, immunology)
  • Macrophage Activation (drug effects)
  • Macrophages (drug effects, enzymology, immunology)
  • Mice
  • Mice, Knockout
  • NF-kappa B (metabolism)
  • Nerve Growth Factors (pharmacology)
  • Netrin-1
  • Neutrophil Infiltration (drug effects)
  • Neutrophils (drug effects, enzymology, immunology)
  • Recombinant Proteins (pharmacology)
  • Reperfusion Injury (enzymology, genetics, immunology, pathology, prevention & control)
  • Time Factors
  • Tumor Suppressor Proteins (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: