title: Protective effects of atorvastatin on chronic allograft nephropathy in rats.
abstract: OBJECTIVE
  Chronic allograft nephropathy (CAN) is the leading cause of late kidney allograft loss. Recent studies have suggested that atorvastatin (ATO) may interact with the acute inflammatory process in the renal interstitium and suppress the proliferation of mesangial cells. We hypothesized that ATO could also inhibit the chronic inflammatory process and prevent the progression of CAN.
  
  
  METHODS
  Fisher (F344) kidneys were orthotopically transplanted into Lewis rat recipients. Lewis-to-Lewis rat kidney transplantation was served as the syngeneic control (Syn group). Allograft recipients were randomized and treated with cyclosporine A alone (Allo group) or in combination with ATO (15 or 30 mg/kg/d intrgastric, respectively, the low dose treatment group/high dose treatment group [LT/HT] groups). Renal function and the urine protein excretion were analyzed. Animals were sacrificed 20 weeks posttransplantation for histological and immunohistochemical studies, as well as analysis of mRNA levels of cytokines and chemokines.
  
  
  RESULTS
  Renal function progressively deteriorated and substantial proteinuria developed in the Allo group compared with the Syn group. ATO-treated rats had significantly higher creatinine clearance rate and less amount of proteinuria. Histological examination revealed obvious features of CAN in the Allo group, whereas LT/HT groups demonstrated minimal glomerulosclerosis, interstitial fibrosis, intimal thickening, and tubular atrophy. The numbers of infiltrating mononuclear cells (ED1+, CD8+, and CD68+) decreased markedly, and the intragraft expression of transforming growth factor beta1 (TGF-beta1) and collagen III were also significantly attenuated in the LT/HT groups, as compared with the Allo group. The mRNA levels of proinflammatory cytokines (interleukin-2, interferon-gamma, interleukin-10), chemokines (RANTES, MCP-1), and profibrotic genes (TGF-beta1, collagen III) were significantly down-regulated in ATO-treated rats.
  
  
  CONCLUSIONS
  Atorvastatin showed excellent favorable effects on blocking renal inflammation and fibrosis, and thus, efficiently inhibited the development and progression of CAN, which might improve the long-term survival rate of renal allografts.
authors.affiliation: Division of Urology and Kidney Transplantation, Nanjing Medical University First Affiliated Hospital, Nanjing, Jiangsu, China. zhangwei@medmail.com.cn
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Yichao
authors.initials: Y
authors.lastname: Wu
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhu
authors.forename: Changjun
authors.initials: C
authors.lastname: Yin
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Gu
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology*; D000069059:Atorvastatin; D018925:Chemokines / Q000235:genetics; D002908:Chronic Disease; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics; D004359:Drug Therapy, Combination; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005355:Fibrosis; D015870:Gene Expression / Q000276:immunology; D006084:Graft Rejection / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D006538:Heptanoic Acids / Q000737:chemistry / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation; D008297:Male; D009000:Monocytes / Q000473:pathology; D011507:Proteinuria / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D000924:Anticholesteremic Agents; D018925:Chemokines; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D006538:Heptanoic Acids; D007166:Immunosuppressive Agents; D011758:Pyrroles; D016572:Cyclosporine; D000069059:Atorvastatin