Fluvastatin attenuates IGF-1-induced ERK1/2 activation and cell proliferation by mevalonic acid depletion in human mesangial cells

The phosphorylation of forkhead transcription factor FOXO3a by Akt is critical regulator of cell proliferation induced by serum. We show that endothelin-1 (ET-1) stimulation of primary human mesangial cells (HMCs) induces βPix and p66Shc up-regulation, resulting in the formation of the βPix/p66Shc complex. In transformed HMCs, ET-1 induces a biphasic phosphorylation of p66Shc and FOXO3a. The second phase leads to p27kip1 down-regulation independently of Akt. Depletion of βPix blocks the second phase of p66Shc and FOXO3a phosphorylation and prevents p27kip1 down-regulation induced by ET-1. Depletion of either βPix or p66Shc inhibits ET-1–induced cell proliferation. The expression of β1Pix induces FOXO3a phosphorylation through activation of Rac1, ERK1/2, and p66Shc. Using either p66Shc- or Akt-depleted cells; we show that β1Pix-induced FOXO3a phosphorylation requires p66Shc but not Akt. β1Pix-induced p27kip1 down-regulation was blocked by U0126 but not by wortmannin. Endogenous βPix and FOXO3a are constitutively associated with endogenous p66Shc. FOXO3a and p66Shc binding requires β1Pix homodimerization. Expression of β1Pix homodimerization deficient mutant abrogates β1Pix-induced p27kip1 down-regulation and cell proliferation. Our results identify p66Shc and FOXO3a as novel partners of β1Pix and represent the first direct evidence of β1Pix in cell proliferation via Erk/p66Shc-dependent and Akt-independent mechanisms.

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CCR7 Is Important for Mesangial Cell Physiology and Repair

Journal of Histochemistry & Cytochemistry ◽

10.1369/0022155417737975 ◽

2017 ◽

Vol 66 (1) ◽

pp. 7-22 ◽

Cited By ~ 2

Author(s):

Simone Wurm ◽

Andreas Steege ◽

Eva-Maria Rom-Jurek ◽

Claudia R. van Roeyen ◽

Armin Kurtz ◽

...

Keyword(s):

Cell Proliferation ◽

Chemokine Receptor ◽

Mesangial Cell ◽

Mesangial Cells ◽

Receptor Expression ◽

Cell Physiology ◽

Lymphoid Tissues ◽

Human Mesangial Cells ◽

Proliferation Assays ◽

First Time

The homeostatic chemokine receptor CCR7 serves as key molecule in lymphocyte homing into secondary lymphoid tissues. Previous experiments from our group identified CCR7 also to be expressed by human mesangial cells. Exposing cultured human mesangial cells to the receptor ligand CCL21 revealed a positive effect on these cells regarding proliferation, migration, and survival. In the present study, we localized CCR7 and CCL21 during murine nephrogenesis. Analyzing wild-type and CCR7 deficient (CCR7–/–) mice, we observed a retarded glomerulogenesis during renal development and a significantly decreased mesangial cellularity in adult CCR7–/– mice, as a consequence of less mesangial cell proliferation between embryonic day E17.5 and week 5 postpartum. Cell proliferation assays and cell-wounding experiments confirmed reduced proliferative and migratory properties of mesangial cells cultured from CCR7–/– kidneys. To further emphasize the role of CCR7 as important factor for mesangial biology, we examined the chemokine receptor expression in rats after induction of a mesangioproliferative glomerulonephritis. Here, we demonstrated for the first time that extra- and intraglomerular mesangial cells that were CCR7-negative in control rats exhibited a strong CCR7 expression during the phase of mesangial repopulation and proliferation.

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