Effects Of The Uremic Toxin P-Cresyl Sulfate On Cardiovascular System

Background and ObjectiveChronic kidney disease(CKD)is a major risk factor for the development of cardiovascular disease(CVD),which accounts for 40%-50%all cause mortality.CKD patients endured servere cardiac remodeling and atherosclerosis,which might eventually lead to CVD-related complications such as chronic heart failure and ischemic heart disease.Among CKD population,over 40%of the patients suffered left ventricular hypertrophy(LVH)with alterations of cardiac structure and function;atherosclerosis attacked 30%of CKD patients and deteriorated with the worsening of the renal function.However,the high prevalence of traditional cardiovascular risk factors(e.g.hypertension,hyperlipidema,and diabetes)does not fully explain this augmented cardiovascular risk.Therefore,there must be other risk factors for CVD.CKD is characterized by progressive loss of glomerular filtration rate.Impaired urinary excretion of metabolites leads to accumulation of various uremic toxins,whose cardiovascular toxicity has received wide attention.Chronic hemodialysis and peritoneal dialysis treatments are potent and inefficient approaches to removing most free water-soluble compounds,but that is not the case for protein-bound low-molecular-weight solutes(e.g.phenols,indoles,hippurates,polyamines,advanced glycation end products and homocysteine).p-Cresyl sulfate(PCS)is one of such solutes and has been found to associate with cardiovascular mortality in clinical studies.Despite the clear clinical evidence addressing this correlation,the pathophysiology underlying the development and progression of cardiovascular impairment following renal dysfunction remains to be elucidated.In the present research,we aimed to investigate the mechanisms by which PCS might affect the cardiovascular system.MethodsPART ?1.Experimental mice were randomly divided into 4 groups:sham control,sham treated with PCS,untreated 5/6 nephrectomized(Nx),and PCS-treated 5/6 nephrectomized mice.Transthoracic echocardiography and myocardial sections were used to evaluate the effect of Nx and PCS.2.The cytotoxic effects of PCS on H9c2 cells were studied by flow cytometry,western blot,caspase-3 activity assay and immunofluorescence technique.The effects of NAC and apocynin were also investigated.3.Transthoracic echocardiography was used to evaluate the therapeutic potentials of apocynin.PART ?1.Male apoE-/-mice aged 5 weeks underwent 5/6 nephrectomy and were then randomly divided into two groups:vehicle-treated group and PCS-treated group.After 8 weeks of treatment,invival microscope and western blot were used to study leukocyte-endothelium interaction.Mice were sacrificed for subsequent oil red o staining of the aorta.2.After 24 weeks of treatment,mice underwent histological staining on the sections of the aortic roots.Oil red O,MOMA-2,a-SMA,sirus red,MMP-2 and MMP-9 staining were performed to study the contents and stability of the formed aortic plaques.3.Rat aortic VSMCs were isolated and cell migration was assessed using Transwell plates.The expression of MMPs and TIMPs were detected by western blot.ResultsPART ?1.In Nx mice,PCS promoted the occurrence of cardiac injury and apoptosis.The cardiac function was also altered,manifested by the changes of E/A ratio.Apocynin,a NADPH oxidase inhibitor,mitigated this dysfunction.2.500 or 1000 ?M promoted the apoptosis of H9c2 cells by activating the expression of NADPH oxidase subunits(p22phox and p47phox)and ROS production.Apocynin and NAC partially restored the PCS-induced detrimental effects.PART ?1.PCS administration promoted the growth of atherosclerosis after 8 weeks of treatment.PCS upregulated the expression of adhesion molecules and facilitated the interaction between leukocytes and endothelium.After 24 weeks of treatment,PCS altered the components of the plaques,enhancing their vulnerability.2.PCS activated the migration of VSMCs and caused the imbalance between MMPs and TIMPs.Conclusion1.The uremic toxin PCS disturbed the cellular redox ballance and contributed to detrimental cardiac effects in cell culture.Animal experiments confirm the adverse effects of PCS in cardiomyocytes.Such factors are attributable to the presence of diastolic dysfunction observed by echocardiography.2.PCS promoted atherosclerotic lesion formation and induced plaque instability.These effects might be attributed to enhanced leukocyte-endothelium interaction and the alteration of phenotype in VSMCs.