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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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Effect of netrin-1 administration in ischemia reperfusion-induced apoptosis. Apoptotic cells were identified using TUNEL staining (top panel). Sham.operated wild-type (WT) and RAG-1 knockout mouse kidney did not show any apoptotic cells. Twenty.four hours after reperfusion, the number of apoptotic cells (blue staining) was increased dramatically in WT as well as RAG-1 knockout mice but was decreased with administration of netrin-1. Bottom Panel. Quantification of apoptotic cells. Apoptotic-positive cells were counted in eight random 40X fields. *, p<0.001 vs. sham-operated. #, p<0.001 vs. IR. n=4-6. Scale Bar: 50μM.
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Figure 3: Effect of netrin-1 administration in ischemia reperfusion-induced apoptosis. Apoptotic cells were identified using TUNEL staining (top panel). Sham.operated wild-type (WT) and RAG-1 knockout mouse kidney did not show any apoptotic cells. Twenty.four hours after reperfusion, the number of apoptotic cells (blue staining) was increased dramatically in WT as well as RAG-1 knockout mice but was decreased with administration of netrin-1. Bottom Panel. Quantification of apoptotic cells. Apoptotic-positive cells were counted in eight random 40X fields. *, p<0.001 vs. sham-operated. #, p<0.001 vs. IR. n=4-6. Scale Bar: 50μM.

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)

Effect of netrin-1 administration in ischemia reperfusion-induced apoptosis. Apoptotic cells were identified using TUNEL staining (top panel). Sham.operated wild-type (WT) and RAG-1 knockout mouse kidney did not show any apoptotic cells. Twenty.four hours after reperfusion, the number of apoptotic cells (blue staining) was increased dramatically in WT as well as RAG-1 knockout mice but was decreased with administration of netrin-1. Bottom Panel. Quantification of apoptotic cells. Apoptotic-positive cells were counted in eight random 40X fields. *, p<0.001 vs. sham-operated. #, p<0.001 vs. IR. n=4-6. Scale Bar: 50μM.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Effect of netrin-1 administration in ischemia reperfusion-induced apoptosis. Apoptotic cells were identified using TUNEL staining (top panel). Sham.operated wild-type (WT) and RAG-1 knockout mouse kidney did not show any apoptotic cells. Twenty.four hours after reperfusion, the number of apoptotic cells (blue staining) was increased dramatically in WT as well as RAG-1 knockout mice but was decreased with administration of netrin-1. Bottom Panel. Quantification of apoptotic cells. Apoptotic-positive cells were counted in eight random 40X fields. *, p<0.001 vs. sham-operated. #, p<0.001 vs. IR. n=4-6. Scale Bar: 50μM.
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