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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.

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Netrin-1 administration suppressed inflammation in kidney in response to ischemia reperfusion (IR). Neutrophil infiltration was quantified after staining kidney sections as described in Materials and Methods. A. Top: Neutrophil staining is absent in sham-operated kidney, but is increased after IR. Netrin-1 administration suppressed neutrophil staining. Scale Bar: 50μM. A. Bottom: Quantification of neutrophil staining in kidney. *, p<0.001 vs. all other groups. #, p<0.05 vs. IR. Values are mean ± SEM. n=4. B. Inflammatory mediator expression in kidney analyzed by real-time RT-PCR. Top: WT mice subjected to sham, IR with/without netrin-1 administration. Bottom: RAG-1 knockout mice subjected to sham, IR with/without netrin-1 administration. *, p<0.05 vs. sham. #, p<0.05 vs. IR. Values are mean ± SEM. n=4.
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Figure 2: Netrin-1 administration suppressed inflammation in kidney in response to ischemia reperfusion (IR). Neutrophil infiltration was quantified after staining kidney sections as described in Materials and Methods. A. Top: Neutrophil staining is absent in sham-operated kidney, but is increased after IR. Netrin-1 administration suppressed neutrophil staining. Scale Bar: 50μM. A. Bottom: Quantification of neutrophil staining in kidney. *, p<0.001 vs. all other groups. #, p<0.05 vs. IR. Values are mean ± SEM. n=4. B. Inflammatory mediator expression in kidney analyzed by real-time RT-PCR. Top: WT mice subjected to sham, IR with/without netrin-1 administration. Bottom: RAG-1 knockout mice subjected to sham, IR with/without netrin-1 administration. *, p<0.05 vs. sham. #, p<0.05 vs. IR. Values are mean ± SEM. n=4.

Mentions: Because our previous studies demonstrated that netrin-1 regulates inflammation, we determined whether the protection of kidney function is due to the suppression of inflammation. As shown in Figure 2, neutrophil infiltration and cytokine and chemokine expression were increased in WT and RAG1 mice knockout treated with vehicle. However, administration of netrin-1 suppressed neutrophil infiltration and inflammatory cytokine and chemokine expression (Figure 2). Reduction in inflammation was associated with improvement in histological injury. Moreover, tubular apoptosis was also significantly suppressed (Figure 3). However, the pathway through which netrin-1 suppresses inflammation in ischemic AKI is unknown.


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)

Netrin-1 administration suppressed inflammation in kidney in response to ischemia reperfusion (IR). Neutrophil infiltration was quantified after staining kidney sections as described in Materials and Methods. A. Top: Neutrophil staining is absent in sham-operated kidney, but is increased after IR. Netrin-1 administration suppressed neutrophil staining. Scale Bar: 50μM. A. Bottom: Quantification of neutrophil staining in kidney. *, p<0.001 vs. all other groups. #, p<0.05 vs. IR. Values are mean ± SEM. n=4. B. Inflammatory mediator expression in kidney analyzed by real-time RT-PCR. Top: WT mice subjected to sham, IR with/without netrin-1 administration. Bottom: RAG-1 knockout mice subjected to sham, IR with/without netrin-1 administration. *, p<0.05 vs. sham. #, p<0.05 vs. IR. Values are mean ± SEM. n=4.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Netrin-1 administration suppressed inflammation in kidney in response to ischemia reperfusion (IR). Neutrophil infiltration was quantified after staining kidney sections as described in Materials and Methods. A. Top: Neutrophil staining is absent in sham-operated kidney, but is increased after IR. Netrin-1 administration suppressed neutrophil staining. Scale Bar: 50μM. A. Bottom: Quantification of neutrophil staining in kidney. *, p<0.001 vs. all other groups. #, p<0.05 vs. IR. Values are mean ± SEM. n=4. B. Inflammatory mediator expression in kidney analyzed by real-time RT-PCR. Top: WT mice subjected to sham, IR with/without netrin-1 administration. Bottom: RAG-1 knockout mice subjected to sham, IR with/without netrin-1 administration. *, p<0.05 vs. sham. #, p<0.05 vs. IR. Values are mean ± SEM. n=4.
Mentions: Because our previous studies demonstrated that netrin-1 regulates inflammation, we determined whether the protection of kidney function is due to the suppression of inflammation. As shown in Figure 2, neutrophil infiltration and cytokine and chemokine expression were increased in WT and RAG1 mice knockout treated with vehicle. However, administration of netrin-1 suppressed neutrophil infiltration and inflammatory cytokine and chemokine expression (Figure 2). Reduction in inflammation was associated with improvement in histological injury. Moreover, tubular apoptosis was also significantly suppressed (Figure 3). However, the pathway through which netrin-1 suppresses inflammation in ischemic AKI is unknown.

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