458: Reduced nephrogenesis in low birth offspring is regulated by GDNF signaling dysregulation through the MAPK/ERK signaling pathway

Abstract

ObjectiveGDNF-RET signaling is a critical factor in nephrogenesis and occurs, at least in part, through the canonical MAPK/ERK pathway. Down-regulation of GDNF reduces nephron number and decrement of ERK reduces ureteric branching. Low birthweight offspring resulting from maternal food restricted (MFR) dams have reduced nephron number. We hypothesized that the GDNF signaling pathway would be impacted by MFR programming of developing kidneys.Study DesignFirst-time pregnant Sprague Dawley rat dams were 50% MFR starting at embryonic day (e)10. Kidneys were removed from e20 offspring from MFR and control (C) dams. Kidney mRNA was assessed for GDNF, GDNF receptors RET and GRFα1, and for downstream signaling factors ERK1 and ERK2 by RT-PCR. Protein expression of GDNF, RET, GRFα1, and phosphorylated (p) ERK1 and ERK2 was determined by Western blot.ResultsBoth mRNA and protein expression of GDNF, GRFα1, pERK1 and pERK2 were decreased significantly (p <0.05) in kidneys of MFR offspring. RET was unchanged.ConclusionGDNF downstream signaling is dysregulated in low birthweight MFR offspring, which may be a key mechanism in reduced renal development. This dysregulated GDNF signally is mediated, at least partially, by loss of phosphorylation in the MAPK/ERK pathway. ObjectiveGDNF-RET signaling is a critical factor in nephrogenesis and occurs, at least in part, through the canonical MAPK/ERK pathway. Down-regulation of GDNF reduces nephron number and decrement of ERK reduces ureteric branching. Low birthweight offspring resulting from maternal food restricted (MFR) dams have reduced nephron number. We hypothesized that the GDNF signaling pathway would be impacted by MFR programming of developing kidneys. GDNF-RET signaling is a critical factor in nephrogenesis and occurs, at least in part, through the canonical MAPK/ERK pathway. Down-regulation of GDNF reduces nephron number and decrement of ERK reduces ureteric branching. Low birthweight offspring resulting from maternal food restricted (MFR) dams have reduced nephron number. We hypothesized that the GDNF signaling pathway would be impacted by MFR programming of developing kidneys. Study DesignFirst-time pregnant Sprague Dawley rat dams were 50% MFR starting at embryonic day (e)10. Kidneys were removed from e20 offspring from MFR and control (C) dams. Kidney mRNA was assessed for GDNF, GDNF receptors RET and GRFα1, and for downstream signaling factors ERK1 and ERK2 by RT-PCR. Protein expression of GDNF, RET, GRFα1, and phosphorylated (p) ERK1 and ERK2 was determined by Western blot. First-time pregnant Sprague Dawley rat dams were 50% MFR starting at embryonic day (e)10. Kidneys were removed from e20 offspring from MFR and control (C) dams. Kidney mRNA was assessed for GDNF, GDNF receptors RET and GRFα1, and for downstream signaling factors ERK1 and ERK2 by RT-PCR. Protein expression of GDNF, RET, GRFα1, and phosphorylated (p) ERK1 and ERK2 was determined by Western blot. ResultsBoth mRNA and protein expression of GDNF, GRFα1, pERK1 and pERK2 were decreased significantly (p <0.05) in kidneys of MFR offspring. RET was unchanged. Both mRNA and protein expression of GDNF, GRFα1, pERK1 and pERK2 were decreased significantly (p <0.05) in kidneys of MFR offspring. RET was unchanged. ConclusionGDNF downstream signaling is dysregulated in low birthweight MFR offspring, which may be a key mechanism in reduced renal development. This dysregulated GDNF signally is mediated, at least partially, by loss of phosphorylation in the MAPK/ERK pathway. GDNF downstream signaling is dysregulated in low birthweight MFR offspring, which may be a key mechanism in reduced renal development. This dysregulated GDNF signally is mediated, at least partially, by loss of phosphorylation in the MAPK/ERK pathway.