Low Dose Ouabain Relieves Kidney And Heart Complications In Type 1 Diabetic Mice And Its Mechanism

In the diabetic state,continuous hyperglycemia can cause diabetic microvascular complications,such as diabetic nephropathy(DN),diabetic cardiomyopathy(DC),neuropathy,retinopathy and other complications.DC and DN are the most common complication of high mortality.About 15-25% of patients with Type 1 diabetes(T1D)and 30-40% of patients with Type2 diabetes(T2D)are affected by DN.In addition,about 65% of diabetics die from heart disease or stroke.High glucose induces the generation of reactive oxygen species(ROS)in cells.Studies find that ROS can trigger the accumulation of polyol metabolic pathways,hexamine metabolic pathways,advanced glycation end products(AGE)accumulation and the protein kinase C(PKC)pathway,leading to oxidative stress,causing damage to cells,tissues,and organs.This ROS / oxidative stress injury is considered to be the "common soil" of diabetic microvascular complications.Therefore,reducing oxidative stress plays an important role in preventing tissue damage from diabetes complications.NFE2 related factor 2(Nrf2)is an important transcription factor that regulates antioxidant activity in the body.The activation of Nrf2 can up-regulate the expression of many downstream antioxidant enzyme genes,which plays an important role in oxidative stress.Endogenous ouabain(EO)is a cardiac glycoside compound.Studies show that its level is increased in many diseases(such as hypertension,renal insufficiency,etc.),so it is considered a hormone drugs induced by stress.In previous studies of the laboratory,it was found that the content of EO in mice with kidney stones increased,and this increase in EO level had kidney protective effects.At the same time,there are many studies show that the level of EO in diabetes is also increased,but its role in diabetes has not been reported,so we used low-dose ouabain to simulate EO in vivo in order to study its role in DN and DC.In this study,C57BL/6 mice were injected intraperitoneally(40 mg/kg,1 m L/100 g)with STZ for 5 consecutive days to establish a mouse model of type 1 diabetes.This subject is to study the effect of low-dose ouabain(0.1 mg/kg)on the damage,function and structural changes of kidney and heart cells in type 1 diabetic mice,and attempts to clarify its mechanism.First,the same dose of normal saline and low-dose ouabain were given to mice in the normal group and diabetic mice,and intraperitoneal injection was performed for 14 weeks to set up four groups: control group(Control),model group(DM),medication group(ouabain),model group + medication group(ouabain + DM).In this study,the fasting blood glucose levels,serum triglyceride levels,and serum cholesterol levels in mice were tested.The results showed that low-dose ouabain can improve glucose metabolism and lipid metabolism in T1 D mice.Through the detection of kidney and heart function indicators and cell damage in mice,it was found that low-dose ouabain can reduce kidney and heart cell damage in T1 D mice and relieve kidney and heart dysfunction.The detection of kidney and heart tissue inflammation,fibrosis-related gene expression and tissue collagen deposition showed that low-dose ouabain significantly reduced the level of inflammation and fibrosis in kidney and heart of T1 D mice.In this study,by detecting the protein level of Nrf2 in mouse kidney and heart tissue and its distribution in cells,it was found that low-dose ouabain can reverse the low expression of Nrf2 in kidney and heart tissues of T1 D mice,while increasing the distribution of Nrf2 in the nucleus Up-regulate the expression of its downstream antioxidant genes,reduce oxidative stress in T1 D mice,and relieve kidney and heart damage.Full text summary: In type 1 diabetic mice,low-dose ouabain treatment was given for 14 consecutive weeks to increase the nuclear expression of Nrf2 in the kidney and heart,reduce oxidative stress induced by high glucose,reduce kidney and heart cell apoptosis,tissue inflammation fibrosis levels,thereby alleviating complications of diabetic nephropathy and heart disease.The innovation and significance of this article: This study found that low-dose ouabain improved renal and cardiac complications in T1 D mice by reducing cellular oxidative stress,and made a preliminary exploration of its mechanism.For the first time,ouabain was used in the study of diabetic complications,which broadened the scope of low-dose ouabain.Because the EO content is low,it is a new endocrine hormone-like substance,so the results of this study also provide a reference for exploring the improvement of EO on the complications of diabetes.