| Background:Health issue attract more and more attention and concern of common people and medical worker,due to the rapid development of the nation's economy.Among of these,chronic kidney disease(CKD)is an important issues of concern.In recent years,a large of studies shows that the morbidity rate of chronic kidney disease have been rising rapidly.Although there are observable and huge progress in healthcare industry,the means to treat chronic kidney disease is very limit and the effect always can not satisfy patient's needs.This situation is a severely and unaffordable economic burden on the entire society and the family of patients,one the other hand,immensely affect the quality of life of patients and their family members.we sincerely hope this research can give a new ideal and way to treat chronic kidney disease.Lots of studies shows that both of wnt/p-catenin signaling and renin-angiotensin system(RAS)make vital difference to the development and progression of renal fibrosis.As the recent studies reported that the components of the RAS,such as the angiotensinogen(AGT),angiotensin converting enzyme(ACE-1),Angiotensin ?(Ang II),Angiotensin II type-1 receptor(AT1R)are regulated directly by Wnt/?-catenin signaling.The previously studies performed by our laboratory shows that the development and progression of renal fibrosis are regulated by intrarenal and circulation system's RAS,but also regulated by cerebral RAS.Simultaneously,the previous studies performed by our laboratory and others positively and effectively established the regulation and backup mechanisms between cerebral and intrarenal RAS.However,the effect and function of wnt/-catenin signaling in cerebral on the renal fibrosis nerve been clarified and the link between wnt/p-catenin signaling and RAS nerve been illustrated.Purpose:This study try to block the cerebral wnt/?-catenin signaling by wnt antagonist to research the function of the cerebral Wnt/?-catenin signaling on renal fibrosis,and to confirm the relationship between cerebral Wnt/?-catenin and RAS.Methods:1.Male Sprague-Dawley rats(156-180)gpurchased from the Nanfang Hospital Animal Experiment Centre and were maintained in a pathogen-free facility under temperature and light controlled conditions(24±2?,12-h dark/light cycle)and 55±5%humidity for at least 1 week prior to the experiments.All animal experiments were approved by the Animals Experiment Ethics Committee of Southern Medical University.Five-sixths nephrectomy and sham operation was performed to establish renal fibrosis model.After 6 weeks of operation,measure body weight,measure blood pressure by the means of tail-cuff,collect vein blood and measure serum creatinine(Scr)and blood urea nitrogen(BUN),and collect 24h urine by metabolism cage and measure the expression level of 24h urine protein.On the basis of the measurements to screen out the rats which meet the requirement and randomly assigned the rats to three groups match for 24h urine protein:(1)sham control.(2)ICV aCSF+5/6NX.(3)ICV DKK1+5/6NX.2.After six weeks of intervention,measure body weight,measure blood pressure by the means of tail-cuff,collect vein blood and measure serum creatinine(Scr)and blood urea nitrogen(BUN),and collect 24h urine by metabolism cage and measure the expression level of 24h urine protein.Sacrifice rats under the condition of general anesthesia by sodium pentobarbital(40 mg/kg,i.p.)and careful and patient collect brain and renal tissues sample for further relevant measure.3.The expression level of wnt/?-catenin signaling and RAS in PVN and renal were measured and evaluated by the methods of western blot and immunohistochemical staining.Immunohistochemical staining was used to measured and evaluated the serious degree of renal fibrosis and the methods of periodic acid-Schiff(PAS)and Sirius red was used to measured and evaluated the serious degree of renal pathologic changes.Result:1.ICV aCSF+5/6NX group rats suffer severely loss of weigh,elevation of systolic blood pressure,elevation of the level of serum creatinine and 24h urine protein,severe change of renal fibrosis and significant glomerular sclerosis compare to sham control group.2.This study clearly show that the abnormal over-expression of intrarenal wnt/?-catenin signaling and RAS is tightly link to renal fibrosis change in 5/6NX rats.Simultaneously,the results show that the abnormal up-regulation of wnt/?-catenin signaling and RAS in cerebral is very severe.3.This study used antagonist of wnt(DKK1)by intracerebroventricular inject(ICV)to block the wnt/?-catenin signaling.The research results show that cerebral wnt/?-catenin signaling and RAS were repressed obviously,such as angiotensinogen(AGT)angiotensin-converting enzyme inhibitor(ACEI)andangiotensin receptor block(ARB),although RAS was not blocked directly by common RAS inhibitor.Simultaneously intrarenal wnt/?-catenin signaling and RAS were repressed clearly which were influenced by cerebral changes of wnt/?-catenin signaling and RAS expression mode.Conclusion:1.Renal fibrosis and other accompanied pathological lesion is closely related to the abnormal change of intrarenal wnt/?-catenin signaling and RAS.Central regulation to kidney make significant difference to the development and progression of renal fibrosis change.2.Cerebral RAS is regulated obviously by cerebral wnt/?-catenin signaling in renal fibrosis rats and Cerebral RAS may regulated by cerebral wnt/?-catenin signaling directly,as the previous studies show in the local of kidney in renal fibrosis animal model. |
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