A Study Of Protective Effects And Mechanisms Of ELABELA On Diabetic Nephtopathy In Mice

Diabetes mellitus,a metabolic disease characterized by hyperglycemia,is mainly caused by insulin resistance and insulin secretion dysfunction.Diabetic nephropathy(DN)is a common complication of diabetes and the leading cause of end-stage renal failure.DN is characterized by a chronic inflammatory response accompanied by metabolic dysfunction and hemodynamic changes.In the early stages of DN,glomerular dysfunction can be observed in the form of a decrease in glomerular filtration rate and albuminuria.Podocytes are terminally differentiated cells required for the maintenance of normal glomerular function.Podocytes are highly specialized cells with poor proliferative ability,and apoptosis-induced podocyte loss is a key driver of progressive glomerular sclerosis.PI3K/ Akt / mTOR signaling pathway is involved in the regulation of various cellular functions,including cell proliferation,differentiation,apoptosis,and glucose transport.Consequently,this pathway is an important target for drugs involved in the protection of kidney cells and for those regulating apoptosis and play an important role in the prevention and treatment of diabetes.Elabela(ELA)is a 32 amino acid polypeptide discovered by Pauli and Chng in 2014.Its expression level peaks during the embryonic period,and then its expression gradually decreases with the growth and development of the individual,and finally its expression can only be detected in the kidney.ELA and Apelin are both ligands of APJ and act by acting on APJ receptors.It can be predicted that they have similar biological functions.Apelin’s protective effect on diabetic nephropathy has been proven before.However,the study on the role of ELA in the physiological and pathological processes of the kidney is still in its infancy,which has great space for exploration and research value.In order to explore the role of ELA in diabetic nephropathy and its related mechanisms.We selected wild-type C57BL/6J mice,and established a diabetes model induced by STZ.ELA was injected subcutaneously for 6 months,and the protective effect of ELA on diabetic nephropathy was observed by detecting indicators of renal general features,inflammatory response and fibrosis.The results showed that ELA significantly reduced proteinuria,renal inflammatory response and fibrosis in diabetic mice,and reduced glomerular podocyte apoptosis.Meanwhile,we observed that ELA can activate the inhibited PI3K/ AKT/ mTOR signaling pathway under the condition of DN.In order to further explore the biological role and molecular mechanism of ELA,we performed cell experiments in vitro.We used podocytes under high glucose conditions as a cell model for mimicking type 1 diabetes,and LY294002 was targeted to inhibit the activation of PI3 K and AKT,so as to figure out whether ELA could inhibit high glucose-induced podocyte injury by activating the PI3K/AKT/mTOR signaling pathway.We found that ELA protects podocytes under high glucose conditions and relies on the PI3K/AKT/mTOR signaling pathway.Taken together,we conclude that administration of ELA under diabetic conditions attenuates renal inflammation and fibrosis,reduces apoptosis of glomerular podocytes,and improves renal pathology and renal dysfunction.In addition,ELA provides a protective effect on DN by activating PI3K/Akt/mTOR signaling pathway and reducing podocyte apoptosis,which provides new strategies and ideas for the prevention and treatment of diabetic nephropathy.