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Hyperglycemia: GDNF-EGR1 pathway target renal epithelial cell migration and apoptosis in diabetic renal embryopathy.

Lin CY, Lin TY, Lee MC, Chen SC, Chang JS - PLoS ONE (2013)

Bottom Line: Preliminary study found EGR-1 persistently expressed with GDNF in hyperglycemic environment.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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Immunology Center, China Medical University Hospital, Taichung, Taiwan. cylin@mail.cmuh.org.tw

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.

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Schematic diagram of gene screening involved in hyperglycemia induce fetal nephropathy.We isolated two pairs of mRNA from E11 to E15 of fetal renal tissue either in hyperglycemic or normoglycemic state, then hybridized with 40,000 labeled cDNA microarray target. Differential expression more than twofold was defined as a positive gene (group: gr.).
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pone-0056731-g001: Schematic diagram of gene screening involved in hyperglycemia induce fetal nephropathy.We isolated two pairs of mRNA from E11 to E15 of fetal renal tissue either in hyperglycemic or normoglycemic state, then hybridized with 40,000 labeled cDNA microarray target. Differential expression more than twofold was defined as a positive gene (group: gr.).

Mentions: To pinpoint genes involved in hyperglycemia induced renal embryopathy, we screened 40,000 labelled cDNA targets of microarray. Figure 1 plots schematic diagram of interesting gene screening, with differential expression above two-fold defined as a positive gene. We clustered redundant genes to identify six interesting ones that activate GDNF/MAPK/EGR-1 pathway. Among them, EGR-1 has been demonstrated as a regulatory protein for GDNF and essential for tubulogenesis in hyperglycemia-induced renal embryopathy.


Hyperglycemia: GDNF-EGR1 pathway target renal epithelial cell migration and apoptosis in diabetic renal embryopathy.

Lin CY, Lin TY, Lee MC, Chen SC, Chang JS - PLoS ONE (2013)

Schematic diagram of gene screening involved in hyperglycemia induce fetal nephropathy.We isolated two pairs of mRNA from E11 to E15 of fetal renal tissue either in hyperglycemic or normoglycemic state, then hybridized with 40,000 labeled cDNA microarray target. Differential expression more than twofold was defined as a positive gene (group: gr.).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585314&req=5

pone-0056731-g001: Schematic diagram of gene screening involved in hyperglycemia induce fetal nephropathy.We isolated two pairs of mRNA from E11 to E15 of fetal renal tissue either in hyperglycemic or normoglycemic state, then hybridized with 40,000 labeled cDNA microarray target. Differential expression more than twofold was defined as a positive gene (group: gr.).
Mentions: To pinpoint genes involved in hyperglycemia induced renal embryopathy, we screened 40,000 labelled cDNA targets of microarray. Figure 1 plots schematic diagram of interesting gene screening, with differential expression above two-fold defined as a positive gene. We clustered redundant genes to identify six interesting ones that activate GDNF/MAPK/EGR-1 pathway. Among them, EGR-1 has been demonstrated as a regulatory protein for GDNF and essential for tubulogenesis in hyperglycemia-induced renal embryopathy.

Bottom Line: Preliminary study found EGR-1 persistently expressed with GDNF in hyperglycemic environment.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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Immunology Center, China Medical University Hospital, Taichung, Taiwan. cylin@mail.cmuh.org.tw

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.

Show MeSH
Related in: MedlinePlus