title: Synergistic Effects of Combining Anti-Midkine and Hepatocyte Growth Factor Therapies Against Diabetic Nephropathy in Rats.
abstract: OBJECTIVE
  This study aimed to assess whether synergism could be achieved when combining midkine (MK) antisense oligodeoxynucleotides (anti-MK ODN) and recombinant human hepatocyte growth factor (HGF) in diabetic nephropathy (DN) rat models.
  
  
  METHODS
  Rats were randomized into 6 groups: control, DN rats without treatment, DN rats treated with scrambled ODN, DN rats treated with anti-MK ODN, DN rats treated with HGF and DN rats treated with anti-MK ODN plus HGF. DN models were created by intraperitoneal injection of streptozotocin. Two weeks later, treatments commenced. ODN (1 mg/kg) was intravenously injected weekly for 4 weeks. HGF (500 μg/kg) was subcutaneously injected daily for 4 weeks. Eight weeks later, rats were euthanized. Serum and urine parameters, kidney histopathological injury scores, immunohistochemistry and protein expressions were measured.
  
  
  RESULTS
  Blood glucose, creatinine, blood urea nitrogen and urine albumin were significantly elevated in DN rats. Any single treatment markedly reduced their levels, yet combined treatment decreased them significantly further. Any monotherapy could decrease renal injury score and immunohistochemistry positive percentage, although the most prominent change was displayed in combinational therapy. Western blot showed the expression of MK was significantly elevated in DN rats. Anti-MK ODN suppressed MK significantly. The protein expressions and serum concentrations of transforming growth factor-β1 and connective tissue growth factor between monotherapy and the combined therapy were significant.
  
  
  CONCLUSIONS
  This study demonstrated that combining MK gene suppressing ODN and HGF protein synergistically attenuates renal injury in DN rats. This study may provide a novel avenue for designing future therapeutic regimens against DN.
authors.affiliation: Departments of Metabolic Diseases (XR, HL, PF, JW), Nuclear Medicine (ZM, WZ), and Anatomy (HY), Tianjin Medical University General Hospital, Tianjin, China; and Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenviroment (KX), Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Ren
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Meng
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Ping
authors.initials: P
authors.lastname: Feng
authors.forename: Junwei
authors.initials: J
authors.lastname: Wang
mesh_terms: D000419:Albuminuria; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism; D004357:Drug Synergism; D020868:Gene Silencing; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D000078792:Midkine; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D020319:Oligodeoxyribonucleotides, Antisense; D011994:Recombinant Proteins; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D000078792:Midkine; D017228:Hepatocyte Growth Factor; D003404:Creatinine