Inhibition of MAP-kinase cascade normalizes the proliferation rate of fibroblasts from patients with Type 1 diabetes and nephropathy

Anna Maestroni, Francesca Tentori, Giancarla Meregalli, Daniela Gabellini, Veronica Asnaghi, Dora Ruggieri, Gianpaolo Zerbini

Research output: Contribution to journalArticlepeer-review

Abstract

Faster proliferation rate characterizes human skin fibroblasts from patients with Type 1 diabetes and nephropathy (DN), but the reason of this phenomenon is still unknown. Growth factors control cell proliferation through an intracellular mitogen-activated protein (MAP) kinase cascade. We have examined the effect of the inhibition of MAP kinase/ERK kinase (MEK), a key point of the MAP kinase cascade, on the proliferation rate of fibroblasts from 40 patients with Type 1 diabetes (20 with and 20 without DN) and from 10 nondiabetic participants. Proliferation rate was measured by cell count in the presence or absence of 30 μmol/l of the MEK inhibitor PD 098059. In normal cultural conditions, proliferation rate was faster in fibroblasts from patients with (0.175±0.009×105 cells day-1, mean±S.E.M.) than without DN (0.110±0.009) and in nondiabetic participants (0.094±0.008; ANOVA P5 cells day-1; 55% of reduction) than without DN (0.068±0.006; 38% of reduction) and in nondiabetic participants (0.064±0.006; 32% of reduction), and differences among groups were lost. In parallel, PD 098059 induced a greater reduction of MEK-dependent phosphorylation in lysates of fibroblasts from patients with (73%) than without (40%) DN. In conclusion, the inhibition of MEK normalizes the proliferation rate of fibroblasts from patients with DN, suggesting that the MAP kinase cascade could be involved in this cellular dysfunction.

Original languageEnglish
Pages (from-to)291-296
Number of pages6
JournalJournal of Diabetes and its Complications
Volume19
Issue number5
DOIs
Publication statusPublished - Sep 2005

Keywords

  • Cell proliferation
  • Diabetic nephropathy
  • Human skin fibroblast
  • MAP kinase cascade
  • Type 1 diabetes mellitus

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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