Netrin-1 Overexpression Protects Kidney from Ischemia Reperfusion Injury by Suppressing Apoptosis

Wang, Weiwei; Reeves, W. Brian; Pays, Laurent; Mehlen, Patrick; Ramesh, Ganesan

doi:10.2353/ajpath.2009.090224

Cited by 68 publications

(70 citation statements)

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“…9,12,13,[32][33][34] Cell death by apoptosis is a major contributor of organ dysfunction in these diseases. Currently, there are no effective treatments available to treat ischemia reperfusion injury or chemical-induced organ injury.…”

Section: Discussionmentioning

confidence: 99%

“…11 Overexpression of netrin-1, specifically in proximal tubular epithelial cells, suppressed ischemia reperfusion and nephrotoxin-induced kidney injury and dextran sulfate sodium-induced colon injury by suppressing apoptosis. 12,13 However, the receptor that mediates the protective effects of netrin-1 and the mechanism of protection against cell death are unknown.…”

Section: (Unc5bmentioning

confidence: 99%

“…For assessment of injury, 5-mm sections were stained with periodic acid-Schiff followed by hematoxylin. Tubular injury was assessed in periodic acid-Schiff-stained sections using a semiquantitative scale, 12,15 in which the percentage of cortical tubules showing epithelial cell necrosis, brush border loss, cast formation, and apoptotic bodies in the cortex was assigned a score: 0, normal; 1, ,10%; 2, 10%-25%; 3, 26%-75%; 4, .75%. Sections were scored independently by two investigators who were blinded to the treatment of the animal.…”

Section: Renal Functionmentioning

confidence: 99%

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UNC5B Receptor Deletion Exacerbates Tissue Injury in Response to AKI

Ranganathan

Jayakumar

Navankasattusas

et al. 2014

Journal of the American Society of Nephrology

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Netrin-1 regulates cell survival and apoptosis by activation of its receptors, including UNC5B. However, the in vivo role of UNC5B in cell survival during cellular stress and tissue injury is unknown. We investigated the role of UNC5B in cell survival in response to stress using mice heterozygously expressing the UNC5B gene (UNC5B 2/flox ) and mice with targeted homozygous deletion of UNC5B in kidney epithelial cells (UNC5B 2/flox/GGT-cre ). Mice were subjected to two different models of organ injury: ischemia reperfusion injury of the kidney and cisplatin-induced nephrotoxicity. Both mouse models of UNC5B depletion had normal organ function and histology under basal conditions. After AKI, however, UNC5B 2/flox/GGT-cre mice exhibited significantly worse renal function and damage, increased tubular apoptosis, enhanced p53 activation, and exacerbated inflammation compared with UNC5B 2/flox and wild-type mice. shRNA-mediated suppression of UNC5B expression in cultured tubular epithelial cells exacerbated cisplatin-induced cell death in a p53-dependent manner and blunted Akt phosphorylation. Inhibition of PI3 kinase similarly exacerbated cisplatin-induced apoptosis; in contrast, overexpression of UNC5B reduced cisplatin-induced apoptosis in these cells. Taken together, these results show that the netrin-1 receptor UNC5B plays a critical role in cell survival and kidney injury through Akt-mediated inactivation of p53 in response to stress.

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Section: Discussionmentioning

confidence: 99%

Section: (Unc5bmentioning

confidence: 99%

Section: Renal Functionmentioning

confidence: 99%

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UNC5B Receptor Deletion Exacerbates Tissue Injury in Response to AKI

Ranganathan

Jayakumar

Navankasattusas

et al. 2014

Journal of the American Society of Nephrology

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“…Thus far, the netrin-1-kidney story has been dominated by one laboratory [2][3][4][5][6][7]. Confirmatory information from an independent source is helpful, particularly if the model is a different one and the findings are not quite the same.…”

mentioning

confidence: 99%

“…How does netrin-1 work? To address that issue, Wang et al studied a transgenic model overexpressing netrin-1 in the kidney [5]. Acute ischemia/reperfusion was the model they employed.…”

mentioning

confidence: 99%

Swerving away from diabetic nephropathy by means of divine guidance

Luft

2013

J Mol Med

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The netrins are a class of proteins involved in axon guidance. They are genetically conserved across nematodes, flies, amphibians, and mammals. Structurally, the netrins resemble the basement membrane protein, laminin. The netrins are chemotropic. Netrin attraction is mediated through "deleted in colorectal carcinoma" (cUNC-40/DCC) cell surface receptors, while repulsion requires UNC-5 receptors. Netrin-1 is found in many sites of the central nervous system as well as in the somatic mesoderm, pancreas, and cardiac muscle. More recent research has linked netrin to the development and formation of non-neural tissue, the detection of cancer, and other diseases. Even myocardial infarction, Alzheimer's disease, and kidney diseases have been found to involve netrins, particularly netrin-1 [1]. As a matter of fact, the kidney has one of the highest netrin-1 expressions. With ischemia/reperfusion, netrin-1 protein expression in renal tubular cells increases further and urinary netrin-1 excretion increases accordingly [2]. Netrin-1's appearance in the urine suggested that netrin-1 might serve as an acute kidney injury "biomarker." A survey of 13 patients with acute kidney injury supported that point of view [3].What is netrin-1 doing in the kidney? Further work by the same group initially exploring the role of netrin-1 in the kidney showed that netrin-1 increased renal tubular epithelial cell proliferation and migration through the UNC5B receptor. Moreover, the increase in cell proliferation, but not migration, was mediated via activation of Akt and ERK pathways [4]. How does netrin-1 work? To address that issue, Wang et al. studied a transgenic model overexpressing netrin-1 in the kidney [5]. Acute ischemia/reperfusion was the model they employed. Netrin-1 overexpression exerted a protective effect from acute kidney injury. Mechanisms included preservation of morphology, reduced cytokine expression, and reduced oxidative stress in the kidney of transgenic mice, compared to wild-type mice. The authors concluded that netrin-1 protects renal tubular epithelial cells against ischemia reperfusioninduced injury by increasing proliferation of recovering cells and suppressing apoptosis in injured cells. However, mechanistically, these studies were insufficient.Since the ischemic kidney is particularly prone to reperfusion-elicited inflammation, the group next sought to determine the function of netrin-1 and its receptor UNC5B in renal ischemia-reperfusion-induced inflammation [6]. They reasoned that ischemia/reperfusion injury rests on inflammatory processes. Renal ischemia-reperfusion caused a rapid decrease in serum netrin-1 levels. However, the administration of recombinant netrin-1, before or after renal ischemia-reperfusion, reduced kidney injury, resulted in apoptosis, and lowered monocyte and neutrophil infiltration. Furthermore, the cytokines IL-6, IL-1β, and TNF-α and the chemokines MCP-1, macrophage-derived cytokine, monokine-induced IFN-γ, keratinocyte-derived chemokine, and chemokine with-6-cysteines production were...

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Netrin‐1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin‐Induced Pulmonary Fibrosis

Sun

Zhu

Pan

et al. 2016

Arthritis & Rheumatology

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Objectives Fibrocytes are collagen-producing leukocytes that accumulate in Scleroderma-associated interstitial lung disease (SSc-ILD) via unknown mechanisms. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in Scleroderma has not been explored. This study uses a novel translational platform based on decellularized human lungs to determine whether the scleroderma lung ECM controls fibrocyte development from peripheral blood mononuclear cells. Methods Decellularized scaffolds prepared from healthy and fibrotic Scleroderma lung explants underwent biomechanical evaluation using tensile testing and biochemical analysis using proteomics. Cells from healthy and SSc-ILD subjects were cultured on these scaffolds, and CD45+Pro-ColIα1+ cells meeting criteria for fibrocytes were quantified. The contribution of Netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and via the inhalational administration of bleomycin to Netrin-1+/− mice. Results Compared to control lung scaffold, SSc-ILD lung scaffolds showed aberrant anatomy, enhanced stiffness, and abnormal extracellular matrix composition. Culture of control cells in Scleroderma scaffolds increased Pro-ColIα1+ production, which was stimulated by enhanced stiffness and abnormal ECM composition. SSc-ILD cells demonstrated increased Pro-ColIα1 responsiveness to Scleroderma lung scaffolds, but not enhanced stiffness. Enhanced Netrin-1 expression was seen on CD14lo SSc-ILD cells and antibody mediated Netrin-1 neutralization attenuated CD45+Pro-ColIα1+ detection in all settings. Netrin-1+/− mice were protected from bleomycin induced lung fibrosis and fibrocyte accumulation. Conclusion Factors present in Scleroderma lung matrices regulate fibrocyte accumulation via a Netrin-1-dependent pathway. Netrin-1 regulates bleomycin induced murine pulmonary fibrosis. Netrin-1 might be a novel therapeutic target in SSc-ILD.

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Netrin-1 Overexpression Protects Kidney from Ischemia Reperfusion Injury by Suppressing Apoptosis

Cited by 68 publications

References 35 publications

UNC5B Receptor Deletion Exacerbates Tissue Injury in Response to AKI

UNC5B Receptor Deletion Exacerbates Tissue Injury in Response to AKI

Swerving away from diabetic nephropathy by means of divine guidance

Netrin‐1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin‐Induced Pulmonary Fibrosis

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