TSPO Increases The Blood Pressure In Offspring Of Prenatal Lipopolysaccharide Exposure Via Regulating Its Renal AT₁R Expression

Background:Hypertension and its complications have become the first risk factor that endanger the health of people.Hypertension is the result of the interactions between gene and environment.The environmental factors include not only the external environment but also the intrauterine environment.Modern biology has put forward "the theory of embryonic origin of adult chronic disease",that is,many chronic of adult diseases such as hypertension,diabetes and so on originated from the plasticity of embryo develepment.It has been reported that the incidence of hypertension is closely related to adverse factors stimulation in the development of embryostage.Animal experiments confirmed that prenatal lipopolysaccharide?LPS?exposure results in dysfunction of the renal dopamine D1 receptor?D1R?in offspring,leading to decrease of urinary sodium excretion.D1 R interacts with angiotensin II type 1 receptor?AT₁R?,the balance of two receptor function plays an important role in the urinary sodium excretion and blood pressure regulation.In several rat models of hypertensive,decrease renal D1 R function accompanied by the increased AT1 R function,lead to sodium and water retention.However,it is not clear whether LPS exposure during pregnancy can affect the expression and function of renal AT1 R in offspring.Our previous studies have found that prenatal LPS expose causes increased oxidative stress in the kidney of offspring,which is an important reason promoting the expression and function of AT1 R.However,the reason of oxidative stress is not quite clear.Mitochondria are important participants in oxidative stress.A large number of studies have shown that mitochondrial dysfunction leads to increased reactive oxygen species?ROS?.Prenatal LPS exposure results in increased renal angiotensin II?Ang II?level in offspring,and the high blood pressure induced by Ang II causes up-regulated translocator protein?TSPO?expression in renal proximal tubule?RPT?.TSPO is a mitochondrial outer membrane protein containing 169 amino acids?tryptophan rich?.Renal TSPO expression is increasedin a variety of hypertension rat models,suggesting there is some relationship between renal TSPO and blood pressure.Previous studies have shown that there is a close relationship between renal TSPO and Renin-angiotensin system?RAS?,indicating that TSPO may influence blood pressure by regulating RAS.RAS is an important regulatory system that affects urinary sodium reabsorption and plays a vital role in the regulation of blood pressure.AngII exerts its sodium retention effects through AT1 R.In the animal model of hypertension,for example,SHR and obese hypertension,the increased renal AT1 R expression is an important factor causing the increased blood pressure.However,it is not clear whether reanl TSPO can regulate AT1 R expression and functions.Based on the aboves,we hypothesize that:1.Prenatal LPS exposure increases renal AT1 R expression in offspring,which promotes urinary sodium reabsorption and results in increased blood pressure;2.Maternal LPS exposure results in up-regulated renal TSPO expression in offspring,which enhances the AT1 R expression.Therefore,in this study,we will study renal AT1 R expression and function in offspring of maternal LPS exposure,and make clear the role of TSPO in the regulation of renal AT1 R in offspring of prenatal LPS exposure.Methods:1 Observing baseline blood pressure,urine volume and urinary sodium excretion in offspring.The diuresis and natriuresis effect of Candesartan?AT₁R blocker?were measured through adrenal artery perfusion.The mRNA expression of AT1 R was quantified by Quantitative polymerase chain reaction?QT-PCR?while the protein expression of AT1 R was analysised by Western blot?WB?.2 Immunohistochemistry and immunofluorescence were employed to reveal distribution and subcellular localization of renal TSPO in Sprague-Dawley rat?SD rats?.The mRNA expression of TSPO was quantified by QT-PCR while the protein expression of TSPO was analysised by Western blot?WB?.3 Ro5-4864?TSPO inhibitor?was used to study the effort of TSPO on blood pressure.At 20 weeks of age,offspring of LPS-and saline-treated dams were randomly assigned into two groups:one group that intraperitoneal injection of saline served as control,and the other group intraperitoneal injection of Ro5-4864.Urine was collected in metabolic cages,and 24 h urine volume and sodium excretion were measured.The diuresisand natriuresis effect of Candesartan?AT₁R blocker?were measured through adrenal artery perfusion.The mRNA expression of AT1 R was quantified by QT-PCR while the protein expression of TSPO was analysised by Western blot.Result:1 Compared with offspring in the control group,the blood pressure increased and the urinary sodium excretion decreased in offspring of the LPS group.The increase expression and fuction of renal AT1 R induced urinary sodium retention was an important factor increasing the blood pressure in offspring of prenatal LPS exposure.2 Compared with offspring in the control group,the expression of renal TSPO in offspring of the LPS group was significantly increased.TSPO locates in the mitochondrion in renal proximal tubule?RPT?cells.3 Ro5-4864?TSPO inhibitor?obviously decreased the blood pressure through increased the urinary sodium excretion in offspring of prenatal LPS exposure,this effect is achieved by down-regulation expression of renal AT1 R,and then decreased the effort of candesartan which block urinary sodium reabsorption,suggest TSPO promotes the expression of renal AT1 R in offspring of LPS group.Conclusion:TSPO promotes renal AT1 R expression in offspring of prenatal LPS expose,which results in the increased of urinary sodium retention and blood pressure.