title: Hyperglycemia: GDNF-EGR1 pathway target renal epithelial cell migration and apoptosis in diabetic renal embryopathy.
abstract: Maternal hyperglycemia can inhibit morphogenesis of ureteric bud branching, Glial cell line-derived neurotrophilic factor (GDNF) is a key regulator of the initiation of ureteric branching. Early growth response gene-1 (EGR-1) is an immediate early gene. Preliminary study found EGR-1 persistently expressed with GDNF in hyperglycemic environment. To evaluate the potential relationship of hyperglycemia-GDNF-EGR-1 pathway, in vitro human renal proximal tubular epithelial (HRPTE) cells as target and in vivo streptozotocin-induced mice model were used. Our in vivo microarray, real time-PCR and confocal morphological observation confirmed apoptosis in hyperglycemia-induced fetal nephropathy via activation of the GDNF/MAPK/EGR-1 pathway at E12-E15. Detachment between ureteric branch and metanephrons, coupled with decreasing number and collapse of nephrons on Day 1 newborn mice indicate hyperglycemic environment suppress ureteric bud to invade metanephric rudiment. In vitro evidence proved that high glucose suppressed HRPTE cell migration and enhanced GDNF-EGR-1 pathway, inducing HRPTE cell apoptosis. Knockdown of EGR-1 by siRNA negated hyperglycemic suppressed GDNF-induced HRPTE cells. EGR-1 siRNA also reduced GDNF/EGR-1-induced cRaf/MEK/ERK phosphorylation by 80%. Our findings reveal a novel mechanism of GDNF/MAPK/EGR-1 activation playing a critical role in HRPTE cell migration, apoptosis and fetal hyperglycemic nephropathy.
authors.affiliation: Clinical Immunology Center, China Medical University Hospital, Taichung, Taiwan. cylin@mail.cmuh.org.tw
authors.forename: Ching-Yuang
authors.initials: CY
authors.lastname: Lin
authors.forename: Tze-Yi
authors.initials: TY
authors.lastname: Lin
authors.forename: Min-Chun
authors.initials: MC
authors.lastname: Lee
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Chen
authors.forename: Jeng-Shou
authors.initials: JS
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000235:genetics; D007674:Kidney Diseases / Q000209:etiology* / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009024:Morphogenesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051766:Early Growth Response Protein 1; D051100:Glial Cell Line-Derived Neurotrophic Factor; D012333:RNA, Messenger; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases