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

Ranganathan, Punithavathi; Jayakumar, Calpurnia; Mohamed, Riyaz; Zheng, Dong; Ramesh, Ganesan

doi:10.1038/ki.2012.423

Cited by 94 publications

(95 citation statements)

References 39 publications

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“…Among the inflammatory mediators, PGE2 has a known role in mediating the inflammatory response in various kidney injuries [11, 12, 33, 34]. Blockade of PGE2 production by inhibiting its synthetic enzymes of COX-2 or mPGES-1 could improve many kidney diseases in animals [19, 24, 35-37], suggesting a pathogenic role of COX-2/mPGES-1/ PGE2 pathway in kidney injury.…”

Section: Discussionmentioning

confidence: 99%

Activation of COX-2/mPGES-1/PGE2 Cascade via NLRP3 Inflammasome Contributes to Albumin-Induced Proximal Tubule Cell Injury

Zhuang¹,

Zhao²,

Liang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: The activation of NOD-like receptor family, pyrin domain containing3 (NLRP3) inflammasome has been shown to be positively correlated with the severity of proteinuria in chronic kidney disease (CKD) patients. Prostaglandin E2 (PGE2), an important inflammatory mediator, is also involved in various kidney injuries. The aim of the present study was to investigate the involvement of NLRP3 inflammasome and PGE2 synthetic pathway in albumin-induced renal tubular injury. Methods: Murine proximal tubular cells (mPTCs) were treated with albumin to induce cell injury. NLRP3 siRNA and specific COX-2 inhibitor NS398 were used to define their roles in mediating albumin-induced mPTC injury or the activation of COX-2/mPGES-1/PGE2 cascade. Results: In mPCTs, inhibition of NLRP3 by a small interfering RNA (siRNA) blocked albumin-induced kidney injury molecule 1 (KIM-1) upregulation, inflammatory response, and cell apoptosis. Albumin markedly activated cyclooxygenase-2 (COX-2)/ microsomal prostaglandin E synthase-1 (mPGES-1)/PGE2 pathway in this cell line, an effect largely abolished by NLRP3 silencing at both mRNA and protein levels. More interestingly, blockade of COX-2 using a specific COX-2 inhibitor NS398 markedly inhibited the upregulation of KIM-1 and inflammatory cytokines, and attenuated cell apoptosis in line with blunted PGE2 release following albumin treatment. Conclusions: The findings suggest that COX-2/mPGES-1/PGE2 axis could be activated by albumin in the proximal tubular cells via a NLRP3 inflammasome-mediated mechanism and could thus contribute to proteinuria-related renal tubular cell injury.

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Section: Discussionmentioning

confidence: 99%

Activation of COX-2/mPGES-1/PGE2 Cascade via NLRP3 Inflammasome Contributes to Albumin-Induced Proximal Tubule Cell Injury

Zhuang¹,

Zhao²,

Liang³

et al. 2017

Cell Physiol Biochem

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“…Netrin-1 was the first to be purified and is the best-characterized member. In addition to its involvement in guiding axon migration during embryonic development, netrin-1 functions in organ formation [3][4][5][6] , tumorigenesis [7] , inflammation [8,9] , and anti-apoptotis [10] , as well as being a potential biomarker for renal injury and certain cancers [11,12] . It also promotes the recovery of neuronal function after cerebral ischemia in animal models [13][14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Axon guidance factor netrin-1 and its receptors regulate angiogenesis after cerebral ischemia

Ding

Liao

2014

Neurosci. Bull.

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Neurogenesis and angiogenesis play important roles in functional recovery after ischemic stroke. When cerebral ischemia occurs, axon regeneration can compensate for the loss of apoptotic neurons in the ischemic area. The formation of new blood vessels ameliorates the local decrease in blood supply, enhancing the supply of oxygen and nutrients to newly-formed neurons. New blood vessels also act as a scaffold for the migration of neuroblasts to the infarct area after ischemic stroke. In light of this, researchers have been actively searching for methods to treat cerebral infarction. Netrins were fi rst identifi ed as a family of proteins that mediate axon guidance and direct axon migration during embryogenesis. Later studies have revealed other functions of this protein family. In this review, we focus on netrin-1, which has been shown to be involved in axon migration and angiogenesis, which are required for recovery after cerebral ischemia. Thus, therapies targeting netrin-1 may be useful for the treatment of ischemic stroke.

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“…Adoptive transfer of these genetically modified macrophages preserved kidney function and reduced microvascular platelet deposition in mice with IRI (32). Ranganathan et al found that netrin-1 induced anti-inflammatory M2 macrophage polarization in vitro through activating peroxisome proliferator-activated receptor gamma (PPAR␥)-dependent pathways (104). Adoptive transfer of netrin-1-treated macrophages suppressed inflammation and protected against kidney injury in IRI mice (105).…”

Section: Anti-inflammatory Macrophages Mediate Kidney Repair and Regementioning

confidence: 99%

“…Acute kidney injury caused by ischemia reperfusion or cytotoxic drugs triggers a prominent infiltrate of neutrophils and natural killer cells within hours of tissue injury (72,78,93,104). Monocytes infiltrate the injured kidney shortly after neutrophils, differentiate into macrophages, and contribute to early tubular injury (3).…”

Section: Pro-inflammatory Macrophages Contribute To Kidney Injury Andmentioning

confidence: 99%

Macrophages in Kidney Injury, Inflammation, and Fibrosis

2015

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Macrophages are found in normal kidney and in increased numbers in diseased kidney, where they act as key players in renal injury, inflammation, and fibrosis. Macrophages are highly heterogeneous cells and exhibit distinct phenotypic and functional characteristics in response to various stimuli in the local microenvironment in different types of kidney disease. In kidney tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce pro-inflammatory macrophages, which contribute to further tissue injury, inflammation, and subsequent fibrosis. Apoptotic cells and anti-inflammatory factors in post-inflammatory tissues induced anti-inflammatory macrophages, which can mediate kidney repair and regeneration. This review summarizes the role of macrophages with different phenotypes in kidney injury, inflammation, and fibrosis in various acute and chronic kidney diseases. Understanding alterations of kidney microenvironment and the factors that control the phenotype and functions of macrophages may offer an avenue for the development of new cellular and cytokine/growth factor-based therapies as alternative treatment options for patients with kidney disease.

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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

Cited by 94 publications

References 39 publications

Activation of COX-2/mPGES-1/PGE2 Cascade via NLRP3 Inflammasome Contributes to Albumin-Induced Proximal Tubule Cell Injury

Activation of COX-2/mPGES-1/PGE2 Cascade via NLRP3 Inflammasome Contributes to Albumin-Induced Proximal Tubule Cell Injury

Axon guidance factor netrin-1 and its receptors regulate angiogenesis after cerebral ischemia

Macrophages in Kidney Injury, Inflammation, and Fibrosis

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