| IgA nephropathy(IgAN)is a common primary glomerular disease,accounting for 36.8 ? 54.2% of primary glomerular disease in renal biopsy patients.The clinical course of the disease is variable,often involving renal tubulointerstitial.Studies have shown that up to 40% of IgAN patients can gradually develop glomerular and interstitial fibrosis within 20 to 25 years,and eventually develop into end-stage renal disease(ESDR).Epac1 is a PKA-independent signaling molecule activated by adrenergic stimulation.It is a newly discovered downstream effector molecule of cyclic adenosine monophosphate(cAMP).Epac1 is involved in GDP/GTP exchange and activation of RAS family small G proteins Rap1 and Rap2.Rap-bound GDP is replaced by GTP,to activate Rap,to play an important signaling role.Epac1/Rap1 is a newly discovered pathway in cAMP signaling pathway,which is involved in many cell functions,such as cell adhesion,cell differentiation,cell junction interaction and secretion.Transforming growth factor?1(TGF-?1)is a kind of fibrotic growth factor with many biological effects.it has different expression in different diseases or different stages of the same disease and different tissues,among which the kidney is the most abundant.It can play a key role in activating Mesangial cells and tubular epithelial cells transdifferentiation and inducing extracellular matrix synthesis and deposition through autocrine or paracrine.TGF-?1 is mainly involved in the occurrence and development of glomerular and interstitial fibrosis through TGF-?1/ Smad classical signaling pathway.Studies have shown that tissue fibrosis can inhibit the expression of Epac1,activated Epac1 plays an anti-fibrosis role by inhibiting the expression of type I collagen and type III collagen.in addition,Epac1 also interacts with TGF?-R1.Therefore,it inhibits the phosphorylation and transcriptional activation of Smad2.However,there is no correlation between the expression of Epac1/Rap1 and tubulointerstitial injury in IgAN.The purpose of this study was to study the expression of Epac1,TGF-?1,Rap1 in renal tissue and the levels of TGF-?1 and Rap1 in serum,and to explore the possible mechanism of tubulointerstitial injury in IgAN,in order to find a new index of tubulointerstitial injury in IgAN.ObjectiveTo study the expression of Epac1,Rap1 and TGF-?1 in renal tubulostroma of IgA nephropathy and the contents of Rap1 and TGF-?1 in serum of IgA nephropathy,we explore the possible mechanism of renal tubulointerstitial injury in order to find a new index of renal tubulointerstitial injury in IgAN nephropathy.MethodExperimental group: from 2016.10 to 2018.12,39 children were hospitalized in the Department of Pediatrics,the first affiliated Hospital of Zhengzhou University.39 cases of renal tissue and 30 cases of serum samples of IgA nephropathy were divided into group A(0 points),group B(1?3 points)and group C(4?9 points)according to the score of renal tubulointerstitial tissue.Control group: 15 healthy children's serum samples were selected from outpatient physical examination,and 10 cases of paracancerous renal tissue from pediatric urology patients undergoing radical nephrectomy in our hospital were selected and classified as group D.The clinical data of the experimental group were collected: name,sex,age,urine routine(red blood cell count,pathological tube type,etc.),24-hour urinary protein quantity(urinary total protein quantitative TP,urinary total protein concentration UTP),renal function(blood.Creatinine Scr,urea nitrogen BUN,renal tubular function(urinary NAG enzyme,?2 microglobulin)and so on.The levels of Rap1 and TGF-?1 in serum of 30 children in experimental group and 15 healthy children in control group were detected by ELISA method,and the expression of Epac1,Rap1 and TGF-?1 in renal tissue of 39 cases of experimental group and paracancerous renal tissue group were detected by immunohistochemistry.The results were analyzed by SPSS statistical software.Result1.the levels of Rap1 and TGF-?1 in serum of group A,group B,group C and healthy children control group.There were significant differences in serum TGF-?1 and Rap1 among group A,group B,group C and normal control group(P < 0.05).The level of serum TGF-?1 in group C was significantly higher than that in group A and normal group(P < 0.0083),but there was no significant difference between group B and group C(P ? 0.058)and group A and normal group(P ? 1.000).The levels of Rap1 in serum of group B and C were significantly lower than those of normal group(P < 0.0083),but there was no significant difference between IgA nephropathy group.2.Expression of Epac1,Rap1 and TGF-?1 in renal tissues of group A,group B,group C and group D.There were significant differences in the expression of Epac1,TGF-?1 and Rap1 in renal tubulointerstitial between the four groups(P < 0.05).The expression of Epac1 and Rap1 in IgA nephropathy group was lower than that in normal group,but the expression of TGF-?1 was higher than that in normal group.The expression of Epac1 in group A was higher than that in group B and C(P < 0.005),B group was higher than that in group C and D(P < 0.005),C group was lower than that in group A,group B and group D(P < 0.005).The expression of Rap1 in group A was higher than that in group C(P < 0.005).The expression of),B in group A was lower than that in group D(P < 0.05).The expression of TGF-?1 in group B was higher than that in group D(P < 0.005)(P < 0.005),and the expression of TGF-?1 in group B was higher than that in group D(P < 0.005),and the expression of TGF-?1 in group B was higher than that in group A and group D(P < 0.005),and the expression of TGF-?1 in group B was higher than that in group D(P < 0.01).3.Relationship between Epac1,Rap1,TGF-?1 and Renal Tubular Interstitial injury.The expression of Epac1 and Rap1 in renal tissue,the level of Rap1 in serum and the score of renal tubulointerstitial tissue were significantly higher than those in control group(P < 0.01).TGF-?1 and serum TGF-?1 were positively correlated with renal tubulointerstitial score(P < 0.01).4.Relationship between Epac1,Rap1,TGF-?1 and Clinical Indexes.The expression of Epac1 in renal tissue was negatively correlated with 24-hour urinary protein concentration(P < 0 05),urinary NAG(P < 0 05),urinary ? 2-MG(P < 0 05),serum creatinine(P < 0 01),urea(P < 0 05)and systolic blood pressure(P < 0 01).TGF-?1 was positively correlated with 24 hour urinary protein concentration(P < 0 05),urinary ? 2-MG(P < 0 05),creatinine(P < 0 01),urea(P < 0 01)and systolic blood pressure(P < 0 01).There was no correlation between the expression of Rap1 in renal tissue and clinical indexes.Serum TGF-?1 level was positively correlated with creatinine(P < 0 01),urea(P < 0 01)and systolic blood pressure(P < 0 01).Serum Rap1 level was negatively correlated with 24-hour urinary protein concentration(P < 0 05),urinary NAG(P(P < 0 05),creatinine(P < 0 01)and urea(P < 0 01).5.Relationship between Epac1,Rap1 and TGF-?1 in Renal Tubular Interstitial injury.The expression of Epac1 in renal tissue was positively correlated with the expression of Rap1(r ? 0.425,P < 0.01),negatively correlated with the expression of TGF-?1(r ? 0.669,P < 0.01),and negatively correlated with the level of serum TGF-?1(r ? 0.619,P < 0.01).It was positively correlated with the expression of serum Rap1(r ? 0.708,P < 0.01).The expression of TGF-?1 in renal tissue was positively correlated with TGF-?1 in serum(r ? 0.561,P < 0.01),and the expression of Rap1 in renal tissue was positively correlated with the level of Rap1 in serum(r ? 0.485,P < 0.01).Conclusion1.Epac1,Rap1 and TGF-?1 may be involved in the occurrence and development of renal tubulointerstitial injury in IgAN.TGF-?1 may promote renal tubulointerstitial injury by inhibiting Epac1/Rap1.2.children with high level of serum TGF-?1 and low level of Rap1 have a high risk of renal tubulointerstitial lesions,which can be used as a predictor of renal tubulointerstitial lesions. |
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