Semaphorin 3A inactivation suppresses ischemia-reperfusion-induced inflammation and acute kidney injury.
Recent studies show that guidance molecules that are known to regulate cell migration during development may also play an important role in adult pathophysiologic states. One such molecule, semaphorin3A (sema3A), is highly expressed after acute kidney injury (AKI) in mice and humans, but its pathophysiological role is unknown. Genetic inactivation of sema3A protected mice from ischemia-reperfusion-induced AKI, improved tissue histology, reduced neutrophil infiltration, prevented epithelial cell apoptosis, and increased cytokine and chemokine excretion in urine. Pharmacological-based inhibition of sema3A receptor binding likewise protected against ischemia-reperfusion-induced AKI. In vitro, sema3A enhanced toll-like receptor 4-mediated inflammation in epithelial cells, macrophages, and dendritic cells. Moreover, administration of sema3A-treated, bone marrow-derived dendritic cells exacerbated kidney injury. Finally, sema3A augmented cisplatin-induced apoptosis in kidney epithelial cells in vitro via expression of DFFA-like effector a (cidea). Our data suggest that the guidance molecule sema3A exacerbates AKI via promoting inflammation and epithelial cell apoptosis.
Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia.
Punithavathi
P
Ranganathan
Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia.
Calpurnia
C
Jayakumar
Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia.
Riyaz
R
Mohamed
Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia.
Neal L
NL
Weintraub
Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia gramesh@gru.edu.
Ganesan
G
Ramesh
D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009393:Nephritis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D039942:Neuropilin-1 / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D040121:Semaphorin-3A / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C112510:Cidea protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D039942:Neuropilin-1; D002945:Cisplatin
acute kidney injury; cisplatin; semaphorin3A