title: CXC Chemokine Receptor 4 (CXCR4) Antagonist, a Novel Pathway to Prevent Chronic Allograft Nephropathy.
abstract: BACKGROUND Chronic allograft nephropathy (CAN) remains a major problem for long-term graft survival and different pathways participate in its development. CXC chemokine receptor 4 (CXCR4) is significantly upregulated following renal injury and fibrotic response. We investigated the effect of AMD3100, a CXCR4 antagonist, on the development of CAN in rat models. MATERIAL AND METHODS CAN rat models (n=20) were established using male Fisher 344 to Lewis rats. Rats in the experimental group (n=10) were treated with AMD3100 (1 mg/kg/day subcutaneously, 0-12 weeks), rats in the control group (n=10) were treated with saline. The serum creatinine levels were monitored every week. Kidney grafts were harvested 12 weeks after modeling for histological analysis. We used chronic allograft damage index (CADI) scores to evaluate each group. Q-PCR and Western blotting were used to measure CXCR4, TGF-β1/Smad3 signaling pathway and α-smooth muscle actin (α-SMA) expression in renal allograft tissue. RESULTS CXCR4 expression was increased significantly in the control group which developed intense chronic changes after 12 weeks. Histological changes of CAN in the experimental group were ameliorated by AMD3100 which also had better graft function compare to the control group. AMD3100 significantly blunted the increase in the mRNA expression level of CXCR4, TGF-β1/Smad3, and α-SMA. A significant reduction in TGF-β1 and α-SMA protein content was observed only in the experimental group as shown in a representative Western blot. CONCLUSIONS Based on these findings, CXCR4 expression may mediate in part the development of CAN. AMD3100 may ameliorate histological changes of CAN and maintain better allograft function. It blunts downstream effects of TGF-β1 signaling and fibroblast activation. Therefore, antagonism of CXCR4 may provide a novel way to prevent the development of CAN.
authors.affiliation: Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland).
authors.forename: Yue
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland).
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Urology, Beijing YouAn Hospital, Capital Medical University, Beijing, China (mainland).
authors.forename: Wenrui
authors.initials: W
authors.lastname: Xue
authors.affiliation: Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland).
authors.forename: Song
authors.initials: S
authors.lastname: Zeng
authors.affiliation: Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland).
authors.forename: Zijian
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland).
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland).
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Hu
mesh_terms: D064591:Allografts / Q000473:pathology*; D000818:Animals; D001596:Benzylamines; D003404:Creatinine / Q000097:blood; D000080027:Cyclams; D004195:Disease Models, Animal; D006085:Graft Survival / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000379:methods; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors
chemical_list: D001596:Benzylamines; C486264:Cxcr4 protein, rat; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D003404:Creatinine; C088327:plerixafor
keywords: Kidney Transplantation; Receptors, CXCR4; Transforming Growth Factor beta; Transplantation Tolerance