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Research ArticleEndocrine and Diabetes

Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats

Wei Jing Liu, Shu Hua Xie, Yu Ning Liu, Won Kim, Heung Yong Jin, Sung Kwang Park, Yi Ming Shao and Tae Sun Park
Journal of Pharmacology and Experimental Therapeutics February 2012, 340 (2) 248-255; DOI: https://doi.org/10.1124/jpet.111.186866
Wei Jing Liu
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Shu Hua Xie
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Yu Ning Liu
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Won Kim
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Heung Yong Jin
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Sung Kwang Park
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Yi Ming Shao
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Tae Sun Park
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Abstract

Dipeptidyl peptidase (DPP) IV inhibitors are probably beneficial for preventing diabetic complication and modulating glucagon-like peptide-1 receptor (GLP-1R) expression. The aim of this study was to determine whether the DPP IV inhibitor LAF237 (vildagliptin) has renoprotective qualities in streptozotocin-induced diabetic rats. Diabetic and nondiabetic rats were treated with an oral dose of 4 or 8 mg/kg/day LAF237 or placebo for 24 weeks, and renal injury was observed by light and electron microscopy. We also assessed DPP IV activity, active GLP-1 level, cAMP and 8-hydroxy-deoxyguanosine excretion, and GLP-1R, cleaved caspase 3, and transforming growth factor-β1 (TGF-β1) expression. LAF237 significantly decreased proteinuria, albuminuria, and urinary albumin/creatinine ratio, improved creatinine clearance, and dose-dependently inhibited interstitial expansion, glomerulosclerosis, and the thickening of the glomerular basement membrane in diabetic rats. It is noteworthy that LAF237 markedly down-regulated DPP IV activity and increased active GLP-1 levels, which probably prevented oxidative DNA damage and renal cell apoptosis by activating the GLP-1R and modulating cAMP. Renoprotection was also associated with a reduction in TGF-β1 overexpression. Our study suggests that DPP IV inhibitors may ameliorate diabetic nephropathy as well as reduce the overproduction of TGF-β1. The observed renoprotection is probably attributable to inhibition of DPP IV activity, mimicking of incretin action, and activation of the GLP-1R.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.186866.

  • ABBREVIATIONS:

    DPP
    dipeptidyl peptidase
    GBM
    glomerular basement membrane
    GLP-1
    glucagon-like peptide 1
    GLP-1R
    GLP-1 receptor
    TGF-β1
    transforming growth factor-β1
    8-OhdG
    8-hydroxy-deoxyguanosine
    STZ
    streptozotocin
    HbA1c
    hemoglobin A1c
    PAS
    periodic acid-Schiff
    DM
    diabetic control
    nonDM
    nondiabetic control
    4LAF/8LAF
    treatment with 4 or 8 mg/kg/day LAF237
    PCR
    polymerase chain reaction
    DAPI
    4,6-diamidino-2-phenylindole
    GSI
    glomerulosclerosis index
    %INT
    fractional interstitial area.

  • Received August 11, 2011.
  • Accepted October 21, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 2
1 Feb 2012
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Research ArticleEndocrine and Diabetes

DPP IV Inhibitor in Diabetic Nephropathy

Wei Jing Liu, Shu Hua Xie, Yu Ning Liu, Won Kim, Heung Yong Jin, Sung Kwang Park, Yi Ming Shao and Tae Sun Park
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 248-255; DOI: https://doi.org/10.1124/jpet.111.186866

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Research ArticleEndocrine and Diabetes

DPP IV Inhibitor in Diabetic Nephropathy

Wei Jing Liu, Shu Hua Xie, Yu Ning Liu, Won Kim, Heung Yong Jin, Sung Kwang Park, Yi Ming Shao and Tae Sun Park
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 248-255; DOI: https://doi.org/10.1124/jpet.111.186866
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