Microalbuminuria in Type I diabetes involves a cell membrane abnormality and is associated with a large increase in cardiovascular risk. The hypothesis that the membrane abnormality alters granule exocytosis in neutrophils, which could contribute to the increased incidence of cardiovascular disease, was investigated. PMA-stimulated expression of CD11b and CD69 on neutrophils from normal controls (NC), long-term uncomplicated Type I diabetic control patients (DC) and diabetic nephropathy patients (DN) was determined by fluorescence activated cell scanning. Neutrophils from DN were faster than neutrophils from either NC or DC to exocytose primary granules with CD69 following initial expression of the adhesion molecule CD11b. However, a larger proportion of neutrophils from DN failed to withdraw CD11b from the cell membrane after 90min incubation. The protein kinase C (PKC) inhibitor, bisindolylmaleimide (BIM), showed that a larger proportion of neutrophils from DN, compared with DC or NC, exocytosed primary granules independent of PKC. The calpain inhibitor, E64d, showed that a larger proportion of neutrophils from both groups of diabetic patients, compared with NC, exocytosed primary granules independent of calpain. Cytoskeletal disruption with cytochalasin D had an effect on CD11b and CD69 exocytosis similar to that of BIM and E64d. The pathways controlling granule exocytosis in neutrophils from diabetic patients are abnormal. A change characteristic of DN causes rapid exocytosis of primary granules, and also causes the adhesion molecule CD11b to persist on an increased proportion of neutrophils. This will make an important contribution to increased vascular damage in these patients.
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Research Article|
December 10 2001
Abnormalities in primary granule exocytosis in neutrophils from Type I diabetic patients with nephropathy
Nicholas J.M. FARDON;
Nicholas J.M. FARDON
1Department of Medicine (Nephrology), Medical School, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne NE2 4HH, U.K.
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Robert WILKINSON;
Robert WILKINSON
1Department of Medicine (Nephrology), Medical School, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne NE2 4HH, U.K.
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Trevor H. THOMAS
1Department of Medicine (Nephrology), Medical School, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne NE2 4HH, U.K.
Correspondence: Dr T. H. Thomas (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
May 29 2001
Revision Received:
September 19 2001
Accepted:
October 23 2001
Online ISSN: 1470-8736
Print ISSN: 0143-5221
The Biochemical Society and the Medical Research Society © 2002
2002
Clin Sci (Lond) (2002) 102 (1): 69–75.
Article history
Received:
May 29 2001
Revision Received:
September 19 2001
Accepted:
October 23 2001
Citation
Nicholas J.M. FARDON, Robert WILKINSON, Trevor H. THOMAS; Abnormalities in primary granule exocytosis in neutrophils from Type I diabetic patients with nephropathy. Clin Sci (Lond) 1 January 2002; 102 (1): 69–75. doi: https://doi.org/10.1042/cs1020069
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