Role Of The Kidney NLRP3 Inflammasome In Prenatal LPS-Induced Hypertension In Offspring Rats

Hypertension is the most common chronic disease,as well as the main dangerous factor in cardiovascular and cerebrovascular diseases.Kidney is one of the important endocrine organs in regulating water and electrolyte balance and blood pressure.Our previous findings suggest that prenatal exposure to LPS results in kidney impairment and hypertension,with decreased number of glomeruli,declined renal functionand increased inflammatory factor expression in three-month old offspring rats.Therefore,we hypothesize that kidney inflammation may play an important role in hypertension induced by prenatal exposure to LPS.NLRP3 inflammasome is one of the most characteristic inflammasome of NOD-like receptors,which can induce cell phlogosis and apoptosis,produce large amount of inflammatory mediators,cause severe inflammation.Dopamine can inhibit the activation of NLRP3 inflammasome by binding to dopamine D1 receptors.In this study,the animal model of hypertension induced by LPS during pregnancy was built to study the role of kidney NLRP3 in prenatal LPS-induced hypertension,and the interfering effect of dopamine.The aim of this study is to find a new target for the prevention and treatment of hypertension induced by prenatal LPS exposure.The researches and results are as follows:1.The establishment of animal model of hypertension induced by prenatal exposure to LPS and the effect of DA on blood pressure in offspring rats.30 pregnant rats were randomly divided into three groups,including Control group;LPS group(pregnant rats were injected with LPS 0.4 mg/kg intraperitoneally on the 8th,10 th and 12 th day of pregnancy);DA+LPS group(rats were exposed to the identical experimental scheme with LPS group and injected with dopamine hydrochloride 1mg/kg).The average arterial pressure of offspring rats in LPS group increased significantly compared with Control group.This result showed that the hypertensive animal model induced by LPS during pregnancy was successful.DA treatment reduced the hypertension induced by prenatal LPS exposure.2.Effects of LPS stimulation and DA intervention during pregnancy on renal function and morphology in offspring rats.Blood was taken from abdominal aorta and blood urea nitrogen(BUN),uric acid(UA)and creatinine(Cre)were analyzed,the results show that BUN concentration decreased significantly in LPS group compared with Control group in male offspring rats.No significant difference was found amongall groups in BUN of female offspring rats.UA concentration increased significantly in LPS group of male offspring rats and female offspring rats.No significant difference was found among all groups in blood Cre in both male and female offspring rats.Serum IL-1β and IL-18 concentration in LPS group increased compared with Control group and DA+LPS group.HE staining shows that the glomerular diameter decreased and cysts increased partly,glomerular balloons were adhered partly,there are moderate to severe hyperplasia in glomerular mesangial matrix diffusively of LPS group compared with the control group and the DA+LPS group.The histological features in DA+LPS group were close to Control group showing normal renal histological features.3.Effects of LPS stimulation and DA intervention during pregnancy on renal NLRP3 inflammation mRNA level in offspring rats.The mRNA expression of NLRP3 in the kidney in the LPS group increased significantly compared with the control group,whereas it decreased significantly in DA+LPS group compared with the LPS group.Compared with the control group,the mRNA expression of ASC increased in LPS group in female offspring rats,decreased in DA+LPS group compared with the LPS group.There was no significant difference between the control group and LPS group in male offspring rats.And there was no significant difference in CASP1 mRNA expression in the kidney of three-month old offspring rats among all groups.4.Effects of LPS stimulation and DA intervention during pregnancy on renal NLRP3 inflammation protein expression level in offspring rats.The expression of NLRP3 was mainly in the epithelial cells of proximal tubules and distal tubules,and slightly expressed in glomerulus in the LPS group compared with the control group;the expression of ASC was mainly in the renal tubules and glomerulus;the expression of CASP1(P10)was mainly in the glomerulus of male offspring rats,while in both renal tubules and glomerulus in female offspring rats.The integral optical density(IOD)showed that NLRP3,ASC and CSAP1 expression in the kidney of the LPS groups increased significantly compared with the control group and DA+LPS group in female rats.NLRP3 expression in LPS group increased significantly compared with Control group and LPS group in male rats.The IOD results were consistent with that of western blot.In summary,the present study shows that NLRP3 plays an important role in hypertension induced by prenatal exposure to LPS,and DA pretreatment results in a protective effect on LPS-induced hypertension and renal injuryin offspring rats.