| Background:Uremic is the late stage of various chronic kidney diseases(CKD).Its high prevalence rate,high disability rate and high mortality rate,not only seriously harm human health,but also bring huge economic and social burden.Cardiovascular disease(CVD)is the main cause of death in uremic patients,while uremic cardiomyopathy is the main cause of high mortality of CVD in patients with CKD except vascular calcification.At present,the pathogenesis of uremic cardiomyopathy has not been fully elucidated.Its main pathological features are reduction of myocardial capillaries,deposition of myocardial interstitial myofibril,hypertrophy and degeneration of cardiomyocytes,ventricular remodeling,leading to left ventricular hypertrophy(LVH),cardiac systolic and diastolic dysfunction,Finally,it will inevitably lead to arrhythmia,heart failure and other complications.At present,studies have confirmed that uremic cardiomyopathy is related to persistent chronic inflammation induced by uremic toxins,among which there are many research on NLRP3 inflammations,but the pathogenesis of NLRP3 and uremic cardiomyopathy is still unclear.Objective:To explore the mechanism of NLRP3 gene knockout in improving myocardial remodeling in uremic mice model.Methods:The experimental mice were randomly divided into wild type sham operation group,wild type model group and NLRP3-/-model group.The mice in the sham operation group only underwent laparotomy without nephrectomy,while those in the model group underwent 5/6 nephrectomy to establish a uremic model.Eight weeks after operation,each grop was examined by echocardiography,blood samples were collected to detect the concentration of plasma creatinine and blood urea nitrogen,and cardiac tissues were collected for HE staining and MASSON staining in cardiac tissues,immunofluorescence staining of NLRP3,Caspase-1,IL-1β,IL-18,COLLAGEN-I,BNP in myocardial tissue,and protein expression of NLRP3,Caspase-1,IL-1β,IL-18,COLLAGEN-I and BNP in myocardium were detected by Western-bloting.Results:Compared with the sham operation group,the levels of plasma Scr and BUN in WT Model group and the NLRP3-/-Model group were significantly increased,and there were significant differences(P<0.05),while the concentrations of plasma creatinine(Scr)and urea nitrogen(BUN)in NLRP3-/-Model group were significantly lower than those in WT Model group(P<0.05).Echocardiography showed that there were different degrees of left ventricular hypertrophy in WT Model group compared with WT Sham group,especially LVAWs,LVAWd and LVPWs were significantly increased(P<0.05),there were significant differences in LVPWs among the three groups(P<0.05),and the LVPWs in NLRP3-/-Model group was between the three groups.The ejection fraction(EF)in the sham operation group was significantly higher than that in the model group,and the EF in the NLRP34-Model group was higher than that in the WT Model group,but there was no significant difference.From the E/A and left ventricular isovolumic relaxation time(IVRT),it could be seen that in the sham operation group the left ventricular diastolic function was higher than that in the model group.the NLRP3-/-Model group was between the three groups,and there were significant differences among the three groups(P<0.05).HE staining showed myocardial hypertrophy and MASSON staining showed myocardial interstitial collagen deposition in model group,while that in NLRP3-/-Model group was less than that in WT Model group.The results of immunofluorescence showed that the expressions of NLRP3,Caspase-1,IL-1β,IL-18 and COLLAGEN-I in the cardiac tissues of the model group were significantly increased.Cardiac tissues Western-Blotting detection showed that the expression of NLRP3,Caspase-1,IL-1β,IL-18 and COLLAGEN-I was significantly up-regulated(P<0.01).The expression of these markers in NLRP3-/-Model group was significantly lower than that in WT Model group,and compared with WT Model group and WT Sham group,there were significant differences(P<0.01).In addition,the expression of BNP in WT Model group was significantly higher than that in NLRP3-/-Model group and WT Sham group(P<0.01),while the expression of BNP in NLRP3-/-Model group was higher than that in WT Sham group,but there was no significant difference.Conclusion:NLRP3-/-gene knockout can improve myocardial remodeling in uremic mice model,the mechanism may be related to its suppression of downstream inflammatory mediators mediated by NLRP3 inflammasomes. |
