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Synergistic Effects of Combining Anti-Midkine and Hepatocyte Growth Factor Therapies Against Diabetic Nephropathy in Rats

Purpose 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... Full description

Journal Title: The American journal of the medical sciences 2015, Vol.350 (1), p.47-54
Main Author: Ren, Xiaojun, MD
Other Authors: Li, Hui, MD, PhD , Feng, Ping, MD , Wang, Junwei, MD , Meng, Zhaowei, MD, PhD , Zheng, Wei, MD, PhD , Yang, Hui, PhD , Xu, Ke, PhD
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-9629
Link: https://www.ncbi.nlm.nih.gov/pubmed/26086153
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recordid: cdi_proquest_miscellaneous_1693187914
title: Synergistic Effects of Combining Anti-Midkine and Hepatocyte Growth Factor Therapies Against Diabetic Nephropathy in Rats
format: Article
creator:
  • Ren, Xiaojun, MD
  • Li, Hui, MD, PhD
  • Feng, Ping, MD
  • Wang, Junwei, MD
  • Meng, Zhaowei, MD, PhD
  • Zheng, Wei, MD, PhD
  • Yang, Hui, PhD
  • Xu, Ke, PhD
subjects:
  • Abridged Index Medicus
  • Albuminuria
  • Animals
  • Blood Glucose - drug effects
  • Blood Urea Nitrogen
  • Connective tissue growth factor
  • Creatinine - blood
  • Cytokines - antagonists & inhibitors
  • Cytokines - genetics
  • Diabetic Nephropathies - genetics
  • Diabetic Nephropathies - metabolism
  • Diabetic nephropathy
  • Drug Synergism
  • Gene Silencing
  • Hepatocyte growth factor
  • Hepatocyte Growth Factor - pharmacology
  • Internal Medicine
  • Kidney - drug effects
  • Kidney - metabolism
  • Midkine
  • Oligodeoxyribonucleotides, Antisense - pharmacology
  • Rats
  • Recombinant Proteins - pharmacology
  • Synergism
  • Transforming Growth Factor beta1 - drug effects
  • Transforming Growth Factor beta1 - metabolism
  • Transforming growth factor-β1
ispartof: The American journal of the medical sciences, 2015, Vol.350 (1), p.47-54
description: Purpose 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.
language: eng
source:
identifier: ISSN: 0002-9629
fulltext: no_fulltext
issn:
  • 0002-9629
  • 1538-2990
url: Link


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titleSynergistic Effects of Combining Anti-Midkine and Hepatocyte Growth Factor Therapies Against Diabetic Nephropathy in Rats
creatorRen, Xiaojun, MD ; Li, Hui, MD, PhD ; Feng, Ping, MD ; Wang, Junwei, MD ; Meng, Zhaowei, MD, PhD ; Zheng, Wei, MD, PhD ; Yang, Hui, PhD ; Xu, Ke, PhD
creatorcontribRen, Xiaojun, MD ; Li, Hui, MD, PhD ; Feng, Ping, MD ; Wang, Junwei, MD ; Meng, Zhaowei, MD, PhD ; Zheng, Wei, MD, PhD ; Yang, Hui, PhD ; Xu, Ke, PhD
descriptionPurpose 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.
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subjectAbridged Index Medicus ; Albuminuria ; Animals ; Blood Glucose - drug effects ; Blood Urea Nitrogen ; Connective tissue growth factor ; Creatinine - blood ; Cytokines - antagonists & inhibitors ; Cytokines - genetics ; Diabetic Nephropathies - genetics ; Diabetic Nephropathies - metabolism ; Diabetic nephropathy ; Drug Synergism ; Gene Silencing ; Hepatocyte growth factor ; Hepatocyte Growth Factor - pharmacology ; Internal Medicine ; Kidney - drug effects ; Kidney - metabolism ; Midkine ; Oligodeoxyribonucleotides, Antisense - pharmacology ; Rats ; Recombinant Proteins - pharmacology ; Synergism ; Transforming Growth Factor beta1 - drug effects ; Transforming Growth Factor beta1 - metabolism ; Transforming growth factor-β1
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descriptionPurpose 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.
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1Albuminuria
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3Blood Glucose - drug effects
4Blood Urea Nitrogen
5Connective tissue growth factor
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7Cytokines - antagonists & inhibitors
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13Gene Silencing
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20Oligodeoxyribonucleotides, Antisense - pharmacology
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22Recombinant Proteins - pharmacology
23Synergism
24Transforming Growth Factor beta1 - drug effects
25Transforming Growth Factor beta1 - metabolism
26Transforming growth factor-β1
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titleSynergistic Effects of Combining Anti-Midkine and Hepatocyte Growth Factor Therapies Against Diabetic Nephropathy in Rats
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abstractPurpose 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.
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pmid26086153
doi10.1097/MAJ.0000000000000510