The Role Of Wnt/?-catenin Signaling Pathway In Renal Dysplasia Of The FGR Fetal Rat

Objective:An adverse intrauterine environment impairs kidney development in fetal growth restriction(FGR)offspring and increases the susceptibility to hypertension in adulthood.We previously reported that maternal protein malnutrition resulted in upregulation of the primary cilia components Ift88 and Pkd2,which negatively regulate canonical Wnt signaling,in the kidneys of neonate FGR rats.To explore the mechanism of the fetal origin of renal disease and susceptibility to hypertension,we investigated canonical Wnt signaling and apoptosis regulators in the FGR fetal rat kidney.Methods:At 12 W,serum and 24-h urine were collected to investigate renal function,and blood pressure was recorded.Expression and activity levels of Ift88,Pkd2,Wnt/?-catenin pathway genes,and apoptosis regulators(Bcl-2 and caspase family)in fetal kidneys were analyzed by quantitative PCR and western blotting.Immunofluorescence was used to detect the cellular location of Ift88,?-catenin,and Bax in fetal kidneys.Results:In FGR rats,the renal index and number of nephrons were decreased at E20,until adulthood(12W).In FGR adult offspring,renal functional indices(urea,NAG and urine protein)and blood pressure were increased,indicating renal injury.In FGR fetal kidneys,Ift88 and Pkd2 m RNA and protein expression were significantly increased at E20,whereas Wnt7 a and Wnt7 b expression was significantly decreased and ?-catenin phosphorylation(Ser33/37/T41)was increased.FGR rats exhibited higher expression of the proapoptotic factor Bax,which colocalized with ?-catenin in renal tubules and glomerular epithelial cells.Cleaved caspases 3,8,and 9 were also upregulated.Conclusions:Protein malnutrition during pregnancy causes increased intraflagellar transport in the fetal kidneys,which may inhibit canonical Wnt signaling,lead to a reduction in ?-catenin,activate Bax,and induce caspase-dependent apoptosis,resulting in a lower number of nephron units and ultimately,in fetal kidney damage and hypertension susceptibility in adult life.