GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway
作者： Mallappa Anitha , Chetan Gondha , Roy Sutliff , Alexander Parsadanian , Simon Mwangi
DOI: 10.1172/JCI26295
关键词: Apoptosis 、 Caspase 3 、 Enteric nervous system 、 Endocrinology 、 Glial cell line-derived neurotrophic factor 、 Enteric neuropathy 、 PI3K/AKT/mTOR pathway 、 Diabetes mellitus 、 Caspase 、 Medicine 、 Internal medicine
摘要: Diabetescanresultinlossofentericneuronsandsubsequentgastrointestinalcomplications.�Themecha- nismofentericneuronallossindiabetesisnotknown.�Weexaminedtheeffectsofhyperglycemiaonenteric� neuronalsurvivalandtheeffectsofglialcellline-derivedneurotrophicfactor�(GDNF)�onmodulatingthissur- vival.�Exposureofprimaryentericneuronsto�20�mMglucose�(hyperglycemia)�for�24�hoursresultedinasignifi- cantincreaseinapoptosiscomparedwith�5�mMglucose�(normoglycemia).�Exposureto�20�mMglucoseresulted� indecreasedAktphosphorylationandenhancednucleartranslocationofforkheadboxO3a�(FOXO3a).�Treat- mentofentericneuronswithGDNFamelioratedthesechanges.�Instreptozotocin-induceddiabeticmice,�there� wasevidenceofmyentericneuronalapoptosisandreducedAktphosphorylation.�Diabeticmicehadlossof� NADPHdiaphorase-stainedmyentericneurons,�delayedgastricemptying,�andincreasedintestinaltransit� time.�Thepathophysiologicaleffectsofhyperglycemia�(apoptosis,�reducedAktphosphorylation,�lossofinhib- itoryneurons,�motilitychanges)�werereversedindiabeticglialfibrillaryacidicprotein-GDNF�(GFAP-GDNF)� Tgmice.�Inconclusion,�wedemonstratethathyperglycemiainducesneuronallossthroughareductioninAkt- mediatedsurvivalsignalingandthattheseeffectsarereversedbyGDNF.�GDNFmaybeapotentialtherapeutic� targetforthegastrointestinalmotilitydisordersrelatedtodiabetes.
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