Abstract
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(-/flox)) and mice with targeted homozygous deletion of UNC5B in kidney epithelial cells (UNC5B(-/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(-/flox/GGT-cre) mice exhibited significantly worse renal function and damage, increased tubular apoptosis, enhanced p53 activation, and exacerbated inflammation compared with UNC5B(-/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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acute Kidney Injury / chemically induced
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Acute Kidney Injury / etiology
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Acute Kidney Injury / genetics
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Acute Kidney Injury / pathology*
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Acute Kidney Injury / physiopathology
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Animals
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Apoptosis
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Cells, Cultured
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Cisplatin / toxicity
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Cytokines / biosynthesis
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Cytokines / genetics
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Disease Models, Animal
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Disease Susceptibility
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Gene Expression Regulation
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Genes, p53
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Genotype
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Kidney Tubules, Proximal / metabolism
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Kidney Tubules, Proximal / pathology
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Mice
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Mice, Knockout
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Nerve Growth Factors / physiology
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Netrin Receptors
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Netrin-1
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Organ Specificity
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Phosphorylation
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Protein Processing, Post-Translational
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / pharmacology
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Receptors, Cell Surface / antagonists & inhibitors
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / physiology*
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Receptors, Cytokine / biosynthesis
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Receptors, Cytokine / genetics
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Reperfusion Injury / genetics
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Reperfusion Injury / pathology*
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Reperfusion Injury / physiopathology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Tumor Suppressor Proteins / physiology
Substances
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Cytokines
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Nerve Growth Factors
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Netrin Receptors
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Ntn1 protein, mouse
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RNA, Small Interfering
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Receptors, Cell Surface
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Receptors, Cytokine
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Tumor Suppressor Proteins
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Netrin-1
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Akt1 protein, mouse
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Proto-Oncogene Proteins c-akt
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Cisplatin