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Published in: Diabetologia 7/2004

01-07-2004 | Article

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

Authors: L. Adhikary, F. Chow, D. J. Nikolic-Paterson, C. Stambe, J. Dowling, R. C. Atkins, G. H. Tesch

Published in: Diabetologia | Issue 7/2004

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Abstract

Aims/hypothesis

Inflammation and fibrosis are pathological mechanisms that are partially regulated by cell signalling through the p38 mitogen-activated protein kinase (MAPK) pathway. Elements of the diabetic milieu such as high glucose and advanced glycation end-products induce activation of this pathway in renal cells. Therefore, we examined whether p38 MAPK signalling is associated with the development of human and experimental diabetic nephropathy.

Methods

Immunostaining identified phosphorylated (active) p38 MAPK in human biopsies with no abnormality (n=6) and with Type 2 diabetic nephropathy (n=12). Changes in kidney levels of phosphorylated p38 were assessed by immunostaining and western blotting in mice with streptozotocin-induced Type 1 diabetes that had been killed after 0.5, 2, 3, 4 and 8 months, and in Type 2 diabetic db/db mice at 2, 4, 6 and 8 months of age.

Results

Phosphorylated p38 was detected in some intrinsic cells in normal human kidney, including podocytes, cortical tubules and occasional interstitial cells. Greater numbers of these phosphorylated p38+ cells were observed in diabetic patients, and phosphorylated p38 was identified in accumulating interstitial macrophages and myofibroblasts. A similar pattern of p38 activation was observed in both mouse models of diabetes. In mice, kidney levels of phosphorylated p38 increased (2–6 fold) following the onset of Type 1 and Type 2 diabetes. In both mouse models, interstitial phosphorylated p38+ cells were associated with hyperglycaemia, increased HbA1c levels and albuminuria. Further assessment of streptozotocin-induced diabetic nephropathy showed that interstitial phosphorylated p38+ cells correlated with interstitial fibrosis (myofibroblasts, collagen).

Conclusions/interpretation

Increased p38 MAPK signalling is a feature of human and experimental diabetic nephropathy. Time course studies in mouse models suggest that phosphorylation of p38 plays a pathological role, particularly in the development of interstitial fibrosis.
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Metadata
Title
Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy
Authors
L. Adhikary
F. Chow
D. J. Nikolic-Paterson
C. Stambe
J. Dowling
R. C. Atkins
G. H. Tesch
Publication date
01-07-2004
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 7/2004
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-004-1437-0

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