Study On Association Of Pentraxin 3 And Diabetic Kidney Disease

Background and Objectives:Diabetic kidney disease(DKD)is one of the common microvascular complication of diabetes.Genetic and environmental factors play role in the pathogenesis of DKD.Pentraxin 3(PTX3),the prototype of the long pentraxin group,shares structural homology with short pentraxins such as C-reactive protein(CRP)and serum amyloid P component(SAP).However,in contrast to CRP and SAP,which are produced in the liver,PTX3 is synthesized by extrahepatic tissues and cells in response to inflammatory stimulations.PTX3 is the only member of the long pentraxin group whose expression was measured in renal tissues.PTX3 is an acute-phase glycoprotein,a soluble receptor acting as an opsonin,and it is believed to contribute to innate immunity as well as degenerated and apoptotic cells clearance;PTX3 binds to several ligands and induces the activation of the component pathway,etc.The human PTX3 gene has been localized on chromosome 3 band q25.Interesting,chromosome 3q is suggested to be linked with DKD on the basis of genome-wide scan and linkage analysis.Previous studies have suggested that plasma levels of PTX3 were associated with development of DKD.This is the first study that investigates the association between PTX3 variants and susceptibility to DKD.We also evaluated the expression of PTX3 protein in a rat model of early DKD kidneys.The primary goal of the present study was to assess the relationship between PTX3 and DKD,and to explore new target for early identification,treatment and prevention of DKD,Methods:1.The case-control study included 135 DKD patients,155 non-diabetic kidney disease(NDKD)patients,and 152 normal controls(NC)(N=442).We genotyped eight PTX3 SNPs(rs2305619,rs2120243,rs1456099,rs7634847,rs1840680,rs2316706,rs2316709,and rs7616177)using the multiplex SnaPshot method.2.Streptozotocin was administered to the rats to induce diabetes.After 12 weeks,the urine microalbumin-to-creatinine ratio and protein-to-creatinine ratio were determined to assess whether the early DKD rat model had been successfully established.Next,the early DKD rats were randomly divided into 2 groups:the islet-transplanted group(IT group),and the untreated group(DKD group).All rats were euthanized at 16 weeks.The expression of PTX3 and other indexes of renal injury(Bax,Bcl-2,Caspase-3,NPHS-2,alpha-SMA,and TGF-beta)were measured by western blot and immunohistochemistry staining.Results:1.The genotype of rs2305619 and rs2120243 differed significantly between the DKD and the NDKD groups(p=0.017 and p=0.033,respectively).Patients with the GG variant of rs2305619 showed 4.078-fold higher susceptibility to DKD than those with the AA variant(95%CI=1.370-12.135,p =0.012).Patients with the AA variant of rs2120243 had a lower risk of developing DKD than those with the CC variant(OR=0.213,95%CI=0.055-0.826,p=0.025).2.Haplotype analysis showed the CAGGG haplotype(SNPs:rs2120243-rs2316709-rs7616177-rs2305619-rs1840680)in block 1 was associated with DKD susceptibility in patients with type 2 diabetes(p=0.0319).3.PTX3 was mainly expressed in tubular epithelial cells of kidney.In renal tissue of early DKD rat,the expression of PTX3 decreased significantly(p<0.01)with massive amounts of renal tubular epithelial cell apoptosis.After islet transplantation,the early DKD was reversed with the improvement in renal cell apoptosis and fibrosis.Meanwhile,the expression of PTX3 in renal tubular epithelial cell was significantly higher than that in DKD group(p<0.01).Conclusions:1.Our findings suggested that PTX3 polymorphisms were associated with the risk for DKD.PTX3 genetic variation may contribute to susceptibility to DKD in Chinese patients with type 2 diabetes.2.The expression of PTX3 in a rat model of early DKD kidneys was significantly associated with the renal injury:The expression of PTX3 decreased in renal tubular epithelial cell of early DKD rats,and significantly increased after the reversal of early DKD by islet transplantation.