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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Movement / drug effects
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Early Growth Response Protein 1 / genetics
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Early Growth Response Protein 1 / metabolism
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Embryonic Development / genetics
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Epithelial Cells / metabolism
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Female
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Gene Expression Profiling
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Genome-Wide Association Study
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Glial Cell Line-Derived Neurotrophic Factor / metabolism
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Glial Cell Line-Derived Neurotrophic Factor / pharmacology
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Humans
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Hyperglycemia / complications*
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Hyperglycemia / genetics
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Kidney Diseases / etiology*
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Kidney Diseases / genetics
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Kidney Tubules, Proximal / embryology
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Kidney Tubules, Proximal / metabolism
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Kidney Tubules, Proximal / pathology
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MAP Kinase Signaling System
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Maternal Exposure / adverse effects*
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Morphogenesis / genetics
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Phosphorylation / drug effects
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Pregnancy
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Proto-Oncogene Proteins c-raf / metabolism
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RNA Interference
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Signal Transduction
Substances
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Early Growth Response Protein 1
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Glial Cell Line-Derived Neurotrophic Factor
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RNA, Messenger
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Proto-Oncogene Proteins c-raf
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Mitogen-Activated Protein Kinases
Grants and funding
This work was supported by the grant of National Science council, Taiwan. (NSC94-2314-B309-005 and NSC 96-2314-B-039-050-MY3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.