Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0920646 (renal ischemia)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Netrin-1, a diffusible laminin-related protein, is highly expressed in the kidney. However, the pathophysiological roles of netrin-1 in the kidney are unknown. To address this question directly, we used transgenic mice that overexpress chicken netrin-1 in the kidney. Netrin-1 overexpression was confirmed by real-time RT-PCR and Western blot analysis. Eight-week-old wild-type and transgenic mice were subjected to 26 minutes of renal ischemia followed by reperfusion for 72 hours. Wild-type mice developed more severe renal dysfunction by 24 hours than netrin-1 transgenic mice. Functional improvement was associated with better preservation of morphology, reduced cytokine expression, and reduced oxidative stress in the kidney of transgenic mice as compared with wild-type mice. In addition, both basal and reperfusion-induced cell proliferation were dramatically increased in transgenic kidneys as determined by Ki-67 staining. Interestingly, ischemia reperfusion induced a large increase in apoptosis in wild-type mice but not in netrin-1 transgenic mice that was associated with reduced caspase-3 activation in the transgenic kidney. These results suggest that netrin-1 protects renal tubular epithelial cells against ischemia reperfusion-induced injury by increasing proliferation and suppressing apoptosis.
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PMID:Netrin-1 overexpression protects kidney from ischemia reperfusion injury by suppressing apoptosis. 1970 Jul 47

Overwhelming evidence suggests that ischemia-reperfusion injury of the kidney is an inflammatory disease mediated by innate and adoptive immune systems. The neuronal guidance molecule netrin-1 was shown to modulate inflammatory responses. Given that ischemic kidney is particularly prone to reperfusion-elicited inflammation, we sought to determine the function of netrin-1 and its receptor UNC5B in ischemia-reperfusion-induced inflammation. Renal ischemia-reperfusion caused a rapid decrease in serum netrin-1 levels. Administration of recombinant netrin-1 before or after renal ischemia-reperfusion reduced kidney injury, apoptosis, monocyte and neutrophil infiltration, and cytokine (IL-6, IL-1beta, and TNF-alpha) and chemokine (MCP-1, macrophage-derived cytokine, monokine-induced IFN-gamma, keratinocyte-derived chemokine, and chemokine with 6 cysteines) production. Analysis for different netrin-1 receptors on leukocytes showed very high expression of UNC5B but not UNC5C, UNC5D, neogenin, or deleted in colorectal cancer. Expression of UNC5A was low. Neutralization of UNC5B receptor reduced netrin-1-mediated protection against renal ischemia-reperfusion injury, and it increased monocyte and neutrophil infiltration, as well as serum and renal cytokine and chemokine production, with increased kidney injury and renal tubular cell apoptosis. Finally, investigation into netrin-1's effect on CD4 T cell stimulation showed suppression of Th1/Th2/Th17 cytokine (IL-2, IL-6, IL-10, IL-13, IL-17, IFN-gamma, IL-4, and TNF-alpha) production in vitro. Our studies demonstrate that netrin-1 acting through UNC5B receptor reduces renal ischemia-reperfusion injury and its associated renal inflammation.
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PMID:Netrin-1 regulates Th1/Th2/Th17 cytokine production and inflammation through UNC5B receptor and protects kidney against ischemia-reperfusion injury. 2069 23

The netrin family of secreted proteins provides migrational cues in the developing central nervous system. Recently, netrins have also been shown to regulate diverse processes beyond their functions in the brain, incluing the ochrestration of inflammatory events. Particularly netrin-1 has been implicated in dampening hypoxia-induced inflammation. Here, we hypothesized an anti-inflammatory role of endogenous netrin-1 in acute kidney injury (AKI). As homozygous deletion of netrin-1 is lethal, we studied mice with partial netrin-1 deletion (Ntn-1(+/-) mice) as a genetic model. In fact, Ntn-1(+/-) mice showed attenuated Ntn-1 levels at baseline and following ischemic AKI. Functional studies of AKI induced by 30 min of renal ischemia and reperfusion revealed enhanced kidney dysfunction in Ntn-1(+/-) mice as assessed by measurements of glomerular filtration, urine flow rate, urine electrolytes, serum creatinine and creatinine clearance. Consistent with these findings, histological studies indicated a more severe degree kidney injury. Similarly, elevations of renal and systemic inflammatory markers were enhanced in mice with partial netrin-1 deficiency. Finally, treatment of Ntn-1(+/-) mice with exogenous netrin-1 restored a normal phenotype during AKI. Taking together, these studies implicate endogenous netrin-1 in attenuating renal inflammation during AKI.
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PMID:Partial netrin-1 deficiency aggravates acute kidney injury. 2162 83

Netrin-1 has been found to protect kidneys from ischemia/reperfusion injury. In this study, we aimed to address whether the protective effects were mediated through suppression of oxidative stress and neuropeptide Y. Compared to sham-operated animals, animals after ischemia/reperfusion showed marked kidney damage and significantly increased levels of serum creatinine, blood urea nitrogen, malondialdehyde, and neuropeptide Y. Renal myeloperoxidase activity was elevated in animals with ischemia/reperfusion relative to sham-operated animals, whereas renal superoxide dismutase activity was reduced. Netrin-1 pretreatment attenuated ischemia/reperfusion-induced functional and pathological changes in the kidney. Moreover, the ischemia/reperfusion-induced changes in the oxidative stress biomarkers and neuropeptide Y were significantly counteracted by prior administration of netrin-1. Taken together, our data showed that netrin-1 pretreatment prevented renal ischemia/reperfusion injury, at least partially through reduction of oxidative stress and neuropeptide Y expression.
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PMID:Netrin-1 pretreatment protects rat kidney against ischemia/reperfusion injury via suppression of oxidative stress and neuropeptide Y expression. 2333 40