title: Synergistic effects of leflunomide and benazepril in streptozotocin-induced diabetic nephropathy.
abstract: BACKGROUND
  Leflunomide (LEF) and benazepril have renoprotective effects on diabetic nephropathy (DN) through their anti-inflammatory and anti-fibrotic activities. This study investigated whether combined treatment using LEF and benazepril affords superior protection compared with the respective monotherapies.
  
  
  METHODS
  Diabetes was induced with streptozotocin (STZ, 65 mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 12 weeks with LEF (10 mg/kg), benazepril (10 mg/kg), or a combination of both. Basic parameters (body weight, fasting blood glucose level, and 24 h urinary protein excretion), histopathology, inflammatory [inflammatory cell infiltration (ED-1), monocyte chemoattractant protein-1 (MCP-1), and Toll-like receptor-2 (TLR-2)] and glomerulosclerotic factors [transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF)], and oxidative stress (8-hydroxy-2'-deoxyguanosine, 8-OHdG) were studied.
  
  
  RESULTS
  Benazepril or LEF treatment significantly prevented body weight loss and 24 h urinary protein excretion induced by diabetes; combined treatment with LEF and benazepril further improved these parameters compared with giving each drug alone (all p < 0.01). Increased expression of inflammatory (MCP-1 and TLR-2) and glomerulosclerotic (TGF-β1 and CTGF) factors in diabetic rat kidney was reduced by treatment with either LEF or benazepril and was further reduced by the combined administration of the two drugs (p < 0.01). These effects were accompanied by suppression of urinary 8-OHdG excretion. There was no significant between-group difference in blood glucose level.
  
  
  CONCLUSIONS
  LEF treatment lessens DN, and combined treatment with LEF and benazepril provides synergistic effects in preventing DN.
authors.affiliation: Nephrology and Dialysis Unit, Department of Internal Medicine, Yanbian University Hospital, Yanji, Jilin Province, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Jin
authors.forename: Shang Guo
authors.initials: SG
authors.lastname: Piao
authors.forename: Ji Zhe
authors.initials: JZ
authors.lastname: Jin
authors.forename: Ying Shun
authors.initials: YS
authors.lastname: Jin
authors.forename: Zhen Hua
authors.initials: ZH
authors.lastname: Cui
authors.forename: Hai Feng
authors.initials: HF
authors.lastname: Jin
authors.forename: Hai Lan
authors.initials: HL
authors.lastname: Zheng
authors.forename: Jin Ji
authors.initials: JJ
authors.lastname: Li
authors.forename: Yu Ji
authors.initials: YJ
authors.lastname: Jiang
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
authors.forename: Can
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000933:Antifibrinolytic Agents / Q000008:administration & dosage; D001552:Benzazepines / Q000008:administration & dosage*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D007555:Isoxazoles / Q000008:administration & dosage*; D000077339:Leflunomide; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000933:Antifibrinolytic Agents; D001552:Benzazepines; D007555:Isoxazoles; D000077339:Leflunomide; C044946:benazepril