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Diabetologia

Erschienen in:

01.08.2003 | Article

Erk 1,2 phosphorylates p27^Kip1: Functional evidence for a role in high glucose-induced hypertrophy of mesangial cells

verfasst von: Dr. G. Wolf, R. Reinking, G. Zahner, R. A. K. Stahl, S. J. Shankland

Erschienen in: Diabetologia | Ausgabe 8/2003

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Abstract

Aims/hypothesis

Mesangial cell hypertrophy is one of the earliest morphological abnormalities of diabetic nephropathy. We have previously shown that high glucose induces p27^Kip1 by a post-transcriptional mechanism and that mesangial cell hypertrophy depends on G₁-phase arrest mediated by this CDK-inhibitor. However, it remains poorly understood how high glucose stimulates p27^Kip1 expression in mesangial cells.

Methods

Mesangial cells were isolated from p27^Kip1 +/+ and –/– mice and characterized by light microscopy and immunohistochemistry. It was tested by Western blotting and autoradiography whether high glucose medium activates Erk 1,2 and whether this activation phosphorylates p27^Kip1. The three consensus phosphorylation sites of p27^Kip1 were mutated and these constructs were expressed in p27^Kip1 –/– mesangial cells. Hypertrophy was assessed by different methods.

Results

High glucose stimulates phosphorylation of MAP kinases Erk 1,2 in p27^Kip1+/+ and –/– mesangial cells. Activation of Erk 1,2 leads to phosphorylation of p27^Kip1in vitro and in vivo. Mutations of serine¹⁰ or threonine¹⁸⁷ still supported high glucose-induced hypertrophy. In contrast, a mutation of serine¹⁷⁸ converted the hypertrophic response into a proliferative phenotype. Mutation of serine¹⁷⁸ leads to the attenuated expression of p27^Kip1 protein in the presence of high glucose.

Conclusions/interpretation

Our study shows that high glucose stimulates Erk 1,2 that phosphorylate p27^Kip1 at serine¹⁷⁸ increasing its expression. This is an important molecular mechanism of high glucose-induced hypertrophy of mesangial cells.

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Titel: Erk 1,2 phosphorylates p27Kip1: Functional evidence for a role in high glucose-induced hypertrophy of mesangial cells
verfasst von: Dr. G. Wolf
R. Reinking
G. Zahner
R. A. K. Stahl
S. J. Shankland
Publikationsdatum: 01.08.2003
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 8/2003
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-003-1163-z

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