Endoplasmic Reticulum Stress Induced Neuronal Apoptosis Plays A Role In Central Diabetes Insipidus After Pituitary Stalk Lesion In Rats

Backgroud:Water-electrolyte and body fluid balance regulation in organisms is vital for the body’s adjustment to external environment.Not only the digestive system and urinary system are involved in the regulation process,central nervous system,especially the hypothalamo-neurohypophyseal system can regulate the water-electrolyte and body fluid balance through integrating multiple organ functions.As an intact waterelectrolyte and body fluid regulation system,any damage to the hypothalamoneurohypophyseal system may cause hypothalamic-neurohypophyseal dysfunction.The most common form is central diabetes insipidus,which also serves as a common clinical complication in neurosurgery department.To figure out the underlying mechanism of pathophysiological change,it’s important to constructed a pathological model of central diabetes insipidus,as well as providing basic scientific evidence for clinical treatment.Objective:1.Establish rat model of the central diabetes insipidus,descripe the laws of development and explore the pathological change of specific hypothalamic nuclei.2.Investigate the regulatory mechanism of pathological changes in the upstream hypothalamic nuclei.3.Search for the drug target to modify specific process and promote the remodeling of the neural function.4.Identify the difference between the acute phase and recovery phase through RNA-seq and bioinformatics anylysis.Methods:1.Central diabetes insipidus was constructed through pituitary stalk electric lesion and the symptoms were evaluated through basic biological parameters2.Examine several vital pathological changes using immunofluorescence and immunoblotting.3.Screen the difference of some key components between the acute phase and recovery phase in central diabetes insipidus based on transcriptome analysis.Results:1.We established the typical triphasic central diabetes insipidus through pituitary stalk electric lesion2.Activation of PI3K/Akt pathway in the acute phase could trigger the endoplasmic reticulum stress-mediated apoptosis.3.We clarified that inhabitation of endoplasmic reticulum stress could partially reverse the apoptosis of AVP neurons and promote neuronal degeneration.4.Based on the transcriptome anlysis,we found the regulatory mechanism of long term recovery,including obesity,inflammation and stress-induced cell senescence.Conclusion:As the kind of hypothalamic injury,in the acute phase of the pituitary stalk injury induced-central diabetes insipidus,endoplasmic reticulum stress induces the apoptosis of neurons in the upstream hypothalamic and lead to the reduction of the number of functional neurons and structural damage.In the recovery phase,stress-induced cell senescence could partially reverse the functional neuron apoptosis through blocking the continuous endoplasmic reticulum stress.However,lasting cell senescence may also lead to further decline of neuroendocrine function and hinder the reconstruction of neuroendocrine function.Our study provides basic experimental evidence of clinical treatment,thus providing a new potential treatment target for central diabetes insipidus as well as hypothalamic injury even central nervous system injury.