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

Ranganathan PV, Jayakumar C, Mohamed R, Dong Z, Ramesh G - Kidney Int. (2013)

Bottom Line: This was associated with reduced apoptosis, inflammatory cytokine and chemokine expression, and improved kidney function.Moreover, netrin-1 regulates COX-2 expression at the transcriptional level through the regulation of NFκB activation.This could be a potential drug for treating many inflammatory immune disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Vascular Biology Center, Georgia Health Sciences University, Augusta, Georgia 30912, USA.

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.

Show MeSH

Related in: MedlinePlus

EP4 agonist increases neutrophil infiltration and exacerbates ischemia reperfusion injury of the kidney. Neutrophil infiltration was quantified after staining the kidney section as described in Materials and Methods. Neutrophil staining was absent in antibody control (A) and sham.operated kidney (B), which is increased after IR (C). Netrin-1 administration suppressed neutrophil infiltration (D). Administration of EP4 agonist abolished netrin-1-mediated suppression of neutrophil infiltration (E). Moreover, administration of EP4 agonist alone exacerbated ischemia reperfusion-induced neutrophil infiltration (F). Quantification of neutrophil infiltration into kidney after different treatments (G). *, p<0.001 vs. sham and netrin-1 treated groups. #, p<0.05 vs. vehicle treated group. Scale Bar: 50μM. H. Kidney function measured by serum creatinine levels. IR-induced kidney dysfunction was suppressed by netrin-1; administration of EP4 agonist exacerbated kidney dysfunction. *, p<0.001 vs. sham and netrin-1 treated groups. #, p<0.05 vs. vehicle treated group. Values are mean ± SEM. n=4-6.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3672333&req=5

Figure 7: EP4 agonist increases neutrophil infiltration and exacerbates ischemia reperfusion injury of the kidney. Neutrophil infiltration was quantified after staining the kidney section as described in Materials and Methods. Neutrophil staining was absent in antibody control (A) and sham.operated kidney (B), which is increased after IR (C). Netrin-1 administration suppressed neutrophil infiltration (D). Administration of EP4 agonist abolished netrin-1-mediated suppression of neutrophil infiltration (E). Moreover, administration of EP4 agonist alone exacerbated ischemia reperfusion-induced neutrophil infiltration (F). Quantification of neutrophil infiltration into kidney after different treatments (G). *, p<0.001 vs. sham and netrin-1 treated groups. #, p<0.05 vs. vehicle treated group. Scale Bar: 50μM. H. Kidney function measured by serum creatinine levels. IR-induced kidney dysfunction was suppressed by netrin-1; administration of EP4 agonist exacerbated kidney dysfunction. *, p<0.001 vs. sham and netrin-1 treated groups. #, p<0.05 vs. vehicle treated group. Values are mean ± SEM. n=4-6.

Mentions: To determine whether netrin-1 suppresses not only COX-2 expression but also PGE2 activity in vivo, we administered PGE2 receptor EP4 selective agonist to WT mice and subjected them to ischemia reperfusion injury. Consistent with the in vitro data, administration of PGE2 receptor EP4 selective agonist (ONO-AE1-329) enhanced ischemic kidney injury and neutrophil infiltration, and netrin-1 did not suppress the EP4 agonist-induced increase in renal injury and neutrophil infiltration (Figure 7). These data suggest and confirm the in vitro findings that netrin-1 regulates COX-2 expression but not PGE2 activity.


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

Ranganathan PV, Jayakumar C, Mohamed R, Dong Z, Ramesh G - Kidney Int. (2013)

EP4 agonist increases neutrophil infiltration and exacerbates ischemia reperfusion injury of the kidney. Neutrophil infiltration was quantified after staining the kidney section as described in Materials and Methods. Neutrophil staining was absent in antibody control (A) and sham.operated kidney (B), which is increased after IR (C). Netrin-1 administration suppressed neutrophil infiltration (D). Administration of EP4 agonist abolished netrin-1-mediated suppression of neutrophil infiltration (E). Moreover, administration of EP4 agonist alone exacerbated ischemia reperfusion-induced neutrophil infiltration (F). Quantification of neutrophil infiltration into kidney after different treatments (G). *, p<0.001 vs. sham and netrin-1 treated groups. #, p<0.05 vs. vehicle treated group. Scale Bar: 50μM. H. Kidney function measured by serum creatinine levels. IR-induced kidney dysfunction was suppressed by netrin-1; administration of EP4 agonist exacerbated kidney dysfunction. *, p<0.001 vs. sham and netrin-1 treated groups. #, p<0.05 vs. vehicle treated group. Values are mean ± SEM. n=4-6.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672333&req=5

Figure 7: EP4 agonist increases neutrophil infiltration and exacerbates ischemia reperfusion injury of the kidney. Neutrophil infiltration was quantified after staining the kidney section as described in Materials and Methods. Neutrophil staining was absent in antibody control (A) and sham.operated kidney (B), which is increased after IR (C). Netrin-1 administration suppressed neutrophil infiltration (D). Administration of EP4 agonist abolished netrin-1-mediated suppression of neutrophil infiltration (E). Moreover, administration of EP4 agonist alone exacerbated ischemia reperfusion-induced neutrophil infiltration (F). Quantification of neutrophil infiltration into kidney after different treatments (G). *, p<0.001 vs. sham and netrin-1 treated groups. #, p<0.05 vs. vehicle treated group. Scale Bar: 50μM. H. Kidney function measured by serum creatinine levels. IR-induced kidney dysfunction was suppressed by netrin-1; administration of EP4 agonist exacerbated kidney dysfunction. *, p<0.001 vs. sham and netrin-1 treated groups. #, p<0.05 vs. vehicle treated group. Values are mean ± SEM. n=4-6.
Mentions: To determine whether netrin-1 suppresses not only COX-2 expression but also PGE2 activity in vivo, we administered PGE2 receptor EP4 selective agonist to WT mice and subjected them to ischemia reperfusion injury. Consistent with the in vitro data, administration of PGE2 receptor EP4 selective agonist (ONO-AE1-329) enhanced ischemic kidney injury and neutrophil infiltration, and netrin-1 did not suppress the EP4 agonist-induced increase in renal injury and neutrophil infiltration (Figure 7). These data suggest and confirm the in vitro findings that netrin-1 regulates COX-2 expression but not PGE2 activity.

Bottom Line: This was associated with reduced apoptosis, inflammatory cytokine and chemokine expression, and improved kidney function.Moreover, netrin-1 regulates COX-2 expression at the transcriptional level through the regulation of NFκB activation.This could be a potential drug for treating many inflammatory immune disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Vascular Biology Center, Georgia Health Sciences University, Augusta, Georgia 30912, USA.

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.

Show MeSH
Related in: MedlinePlus