title: Netrin-1 increases proliferation and migration of renal proximal tubular epithelial cells via the UNC5B receptor.
abstract: The cellular hallmark of kidney repair is a rapid proliferation of renal tubular epithelial cells ultimately leading to the restoration of nephron structure and function. Netrin-1 was discovered as a neural guidance cue and found to be expressed outside the nervous system, including in kidney. Previous work showed that netrin-1 is upregulated in response to ischemic injury and ameliorates ischemic injury. The objectives of this study were to determine the role of netrin-1 in renal tubular epithelial cell proliferation and migration in vitro. Real-time RT-PCR analysis showed that netrin-1 and its receptors UNC5B and neogenin are highly expressed in cultured mouse renal epithelial cells (TKPTS), whereas the expression of the Deleted in Colon Cancer (DCC), UNC5A, UNC5C, and UNC5D receptors is negligible or undetectable. Netrin-1 protein was induced in the edges of mechanical wounds in vitro. Netrin-1 increased TKPTS cell proliferation in a dose-dependent manner. The netrin-1-induced increase in TKPTS cell proliferation was completely prevented by small interfering RNA (siRNA) inhibition of UNC5B receptor but not UNC5C receptor expression. Netrin-1 also increased TKPTS cell migration in vitro, and this was also mediated through the UNC5B receptor. Netrin-1 increased the phosphorylation of Akt and ERK. Inhibition of phosphatidylinositol 3-kinase and MEK1/2 completely inhibited netrin-1-induced cell proliferation but not migration. These results indicate that netrin-1 increases 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.
authors.affiliation: Div. of Nephrology, H040, Penn State Univ. College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.forename: W Brian
authors.initials: WB
authors.lastname: Reeves
authors.forename: Ganesan
authors.initials: G
authors.lastname: Ramesh
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075386:Netrin Receptors; D000075388:Netrin-1; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D000075388:Netrin-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C000617353:Ntn1 protein, mouse; C000617308:Unc5A protein, mouse