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Abnormalities in primary granule exocytosis in neutrophils from Type I diabetic patients with nephropathy

Nicholas J M Fardon1, Robert Wilkinson, Trevor H Thomas

  • 1Department of Medicine (Nephrology), Medical School, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne NE2 4HH, U.K.

Clinical Science (London, England : 1979)
|December 26, 2001
PubMed

Insights

Diabetic nephropathy alters neutrophil function, causing faster granule release and prolonged CD11b expression. These changes in cell membrane abnormalities contribute to increased cardiovascular risk in Type I diabetes.

Area of Science:

  • Immunology
  • Diabetology
  • Cardiovascular Research

Background:

  • Microalbuminuria in Type I diabetes is linked to cell membrane abnormalities and elevated cardiovascular risk.
  • Neutrophil granule exocytosis may be altered by these membrane abnormalities, potentially contributing to cardiovascular disease incidence.

Purpose of the Study:

  • To investigate if cell membrane abnormalities in Type I diabetes alter neutrophil granule exocytosis.
  • To determine the role of protein kinase C (PKC) and calpain pathways in these altered exocytosis processes.

Main Methods:

  • Fluorescence activated cell scanning was used to measure PMA-stimulated CD11b and CD69 expression on neutrophils from normal controls (NC), diabetic controls (DC), and diabetic nephropathy patients (DN).
  • Inhibitors of PKC (bisindolylmaleimide, BIM) and calpain (E64d), as well as cytochalasin D, were used to probe the exocytosis pathways.

Main Results:

  • Neutrophils from DN patients showed faster primary granule exocytosis (CD69 expression) and prolonged CD11b expression compared to NC and DC.
  • A significant proportion of DN neutrophils exhibited PKC- and calpain-independent granule exocytosis.
  • Cytoskeletal disruption mimicked the effects of BIM and E64d on CD11b and CD69 exocytosis.

Conclusions:

  • The pathways controlling neutrophil granule exocytosis are abnormal in diabetic patients, particularly in those with nephropathy.
  • Diabetic nephropathy is characterized by rapid primary granule exocytosis and persistent CD11b expression, contributing to vascular damage.

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