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Clin Exp Nephrol. 2010 Aug;14(4):315-24. doi: 10.1007/s10157-010-0296-x. Epub 2010 Jun 1.

Overexpression of acetyl-coenzyme A carboxylase beta increases proinflammatory cytokines in cultured human renal proximal tubular epithelial cells.

Author information

1
RIKEN Center for Genomic Medicine, Tsurumi-ku, Yokohama, Kanagawa, Japan.

Abstract

BACKGROUND:

We have identified the acetyl-coenzyme A carboxylase beta gene (ACACB) as a strong susceptibility gene to diabetic nephropathy in individuals with type 2 diabetes. To elucidate the mechanism by which ACACB contributes to conferring susceptibility to diabetic nephropathy, we examined the role of ACACB in human renal proximal tubular epithelial cells (RPTECs).

METHODS:

RPTECs were infected with adenovirus vectors encoding ACACB or LacZ (control), and messenger RNA (mRNA) expression profiles were evaluated with a microarray analysis. We determined the mRNA expressions of proinflammatory cytokines by real-time quantitative reverse transcription (RT) polymerase chain reaction (PCR) and secretion of these cytokines from cells by enzyme-linked immunosorbent assay (ELISA).

RESULTS:

Among 54,613 transcripts analyzed in the microarray analysis, genes encoding proinflammatory cytokines, including interleukin (IL)-6, chemokine (C-X-C motif) ligands (CXCL) 1, 2, 5, and 6, were remarkably up-regulated (>20-fold) in the ACACB-overexpressing cells. The increased expression of these inflammatory cytokines was reversed by the addition of a synthetic inhibitor of acetyl-coenzyme A carboxylase beta. Overexpression of ACACB could increase IL-6 mRNA expression and IL-6 protein secretion in a time-dependent manner. We further found that IL-6 mRNA stability and expression had significantly increased in ACACB-overexpressing RPTECs, and a treatment of the cells with p38 mitogen-activated protein kinase (MAPK) inhibitor partially but significantly reversed these effects.

CONCLUSION:

An excess of ACACB results in increased proinflammatory cytokine expression, such as IL-6, at least partly by increasing mRNA stability through a p38 MAPK-dependent pathway.

PMID:
20514549
DOI:
10.1007/s10157-010-0296-x
[Indexed for MEDLINE]

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