Protein Kinase C β Inhibition Attenuates the Progression of Experimental Diabetic Nephropathy in the Presence of Continued Hypertension

  • Darren J. Kelly
    Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, Victoria, Australia
  • Yuan Zhang
    Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, Victoria, Australia
  • Claire Hepper
    Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, Victoria, Australia
  • Renae M. Gow
    Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, Victoria, Australia
  • Kassie Jaworski
    Department of Physiology, University of Melbourne, Parkville, Victoria, Australia
  • Bruce E. Kemp
    St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
  • Jennifer L. Wilkinson-Berka
    Department of Physiology, University of Melbourne, Parkville, Victoria, Australia
  • Richard E. Gilbert
    Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, Victoria, Australia

抄録

<jats:p>In addition to hyperglycemia, hypertension and the renin-angiotensin system have been consistently implicated in the pathogenesis of diabetic nephropathy. Each of these pathogenetic factors may induce changes in cellular function by a common intracellular signaling pathway, the activation of protein kinase C (PKC) β. The present study thus sought to determine the in vivo effect of PKC β inhibition in experimental diabetic nephropathy in the setting of continued hyperglycemia, hypertension, and activation of the RAS. Studies were conducted in the (mRen-2)27 rat, a rodent that is transgenic for the entire mouse renin gene (Ren-2) and develops many of the structural, functional, and molecular characteristics of human diabetic nephropathy when experimental diabetes is induced with streptozotocin (STZ). Six-week-old female Ren-2 rats received an injection of STZ or vehicle and were maintained for 6 months. Within 24 h, diabetic rats were further randomized to receive treatment with the specific PKC β inhibitor, LY333531, admixed in diet (10 mg · kg−1 · d−1) or no treatment (n = 8/group). Diabetic rats developed albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis with a concomitant increase in transforming growth factor-β (TGF-β). Western blot analysis demonstrated increased PKC β in diabetic animals, localized by immunofluorescence to the glomerular mesangium. In vivo inhibition of PKC β with LY333531 led to a reduction in albuminuria, structural injury, and TGF-β expression, despite continued hypertension and hyperglycemia.</jats:p>

収録刊行物

  • Diabetes

    Diabetes 52 (2), 512-518, 2003-02-01

    American Diabetes Association

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