title: UNC5B receptor deletion exacerbates tissue injury in response to AKI.
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.
authors.affiliation: Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia; and.
authors.forename: Punithavathi
authors.initials: P
authors.lastname: Ranganathan
authors.forename: Calpurnia
authors.initials: C
authors.lastname: Jayakumar
authors.forename: Sutip
authors.initials: S
authors.lastname: Navankasattusas
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.forename: Il-man
authors.initials: IM
authors.lastname: Kim
authors.forename: Ganesan
authors.initials: G
authors.lastname: Ramesh
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000209:etiology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D016158:Genes, p53; D005838:Genotype; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000502:physiology; D000075386:Netrin Receptors; D000075388:Netrin-1; D009928:Organ Specificity; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology
chemical_list: D016207:Cytokines; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin