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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 protects kidney from ischemia reperfusion-induced dysfunction. A. Serum creatinine was measured at 24hr after reperfusion in wild-type (WT) and RAG-1 knockout mice subjected to sham operation or ischemia followed by reperfusion (IR) with vehicle or netrin-1 administration. Values are mean ± SEM. *, p < 0.01 vs. all other groups. #, p<0.05 vs. IR; n = 6-8 for each group. B. Tubular necrosis was quantified as described in Materials and Methods. Netrin-1 treatment significantly suppressed ischemia reperfusion induced tubular necrosis in both WT and RAG-1 knockout mice. Values are mean ± SEM. *, p < 0.001 vs. all other groups. #, p<0.05 vs. IR; n = 4-6 for each group.
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Figure 1: Netrin-1 administration protects kidney from ischemia reperfusion-induced dysfunction. A. Serum creatinine was measured at 24hr after reperfusion in wild-type (WT) and RAG-1 knockout mice subjected to sham operation or ischemia followed by reperfusion (IR) with vehicle or netrin-1 administration. Values are mean ± SEM. *, p < 0.01 vs. all other groups. #, p<0.05 vs. IR; n = 6-8 for each group. B. Tubular necrosis was quantified as described in Materials and Methods. Netrin-1 treatment significantly suppressed ischemia reperfusion induced tubular necrosis in both WT and RAG-1 knockout mice. Values are mean ± SEM. *, p < 0.001 vs. all other groups. #, p<0.05 vs. IR; n = 4-6 for each group.

Mentions: Several studies have demonstrated that neutrophils play a major role in mediating acute ischemic kidney injury [2;27]. Our earlier studies also showed that neutrophils are a major subset of that infiltrate after reperfusion injury [9]. However, it was not clear whether netrin-1-mediated protection against ischemia reperfusion injury and suppression of neutrophil infiltration occurs through direct or indirect action on T cells. To determine whether the netrin-1 effect on neutrophils and monocytes is direct and can protect kidney in the absence of T cells, RAG1 knockout mice were subjected to 26 minutes of ischemia followed by reperfusion. As shown in Figure 1, both wild-type (WT) and RAG1 knockout mice developed severe renal injury. Sham-operated WT and RAG1 knockout animals showed no renal dysfunction. Administration of recombinant netrin-1 to both WT and RAG1 knockout mice protected kidney, as shown by a significant reduction in serum creatinine (Figure 1A). Improved kidney function in netrin-1 treated WT and RAG-1 knockout animals was associated with preservation of kidney structure and reduction of tubular necrosis (Figure 1B).


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 protects kidney from ischemia reperfusion-induced dysfunction. A. Serum creatinine was measured at 24hr after reperfusion in wild-type (WT) and RAG-1 knockout mice subjected to sham operation or ischemia followed by reperfusion (IR) with vehicle or netrin-1 administration. Values are mean ± SEM. *, p < 0.01 vs. all other groups. #, p<0.05 vs. IR; n = 6-8 for each group. B. Tubular necrosis was quantified as described in Materials and Methods. Netrin-1 treatment significantly suppressed ischemia reperfusion induced tubular necrosis in both WT and RAG-1 knockout mice. Values are mean ± SEM. *, p < 0.001 vs. all other groups. #, p<0.05 vs. IR; n = 4-6 for each group.
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Figure 1: Netrin-1 administration protects kidney from ischemia reperfusion-induced dysfunction. A. Serum creatinine was measured at 24hr after reperfusion in wild-type (WT) and RAG-1 knockout mice subjected to sham operation or ischemia followed by reperfusion (IR) with vehicle or netrin-1 administration. Values are mean ± SEM. *, p < 0.01 vs. all other groups. #, p<0.05 vs. IR; n = 6-8 for each group. B. Tubular necrosis was quantified as described in Materials and Methods. Netrin-1 treatment significantly suppressed ischemia reperfusion induced tubular necrosis in both WT and RAG-1 knockout mice. Values are mean ± SEM. *, p < 0.001 vs. all other groups. #, p<0.05 vs. IR; n = 4-6 for each group.
Mentions: Several studies have demonstrated that neutrophils play a major role in mediating acute ischemic kidney injury [2;27]. Our earlier studies also showed that neutrophils are a major subset of that infiltrate after reperfusion injury [9]. However, it was not clear whether netrin-1-mediated protection against ischemia reperfusion injury and suppression of neutrophil infiltration occurs through direct or indirect action on T cells. To determine whether the netrin-1 effect on neutrophils and monocytes is direct and can protect kidney in the absence of T cells, RAG1 knockout mice were subjected to 26 minutes of ischemia followed by reperfusion. As shown in Figure 1, both wild-type (WT) and RAG1 knockout mice developed severe renal injury. Sham-operated WT and RAG1 knockout animals showed no renal dysfunction. Administration of recombinant netrin-1 to both WT and RAG1 knockout mice protected kidney, as shown by a significant reduction in serum creatinine (Figure 1A). Improved kidney function in netrin-1 treated WT and RAG-1 knockout animals was associated with preservation of kidney structure and reduction of tubular necrosis (Figure 1B).

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