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.
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.
Authors: Michael Morcos; Ahmed A R Sayed; Angelika Bierhaus; Benito Yard; Rüdiger Waldherr; Wolfgang Merz; Ingrid Kloeting; Erwin Schleicher; Stefani Mentz; Randa F Abd el Baki; Hans Tritschler; Michael Kasper; Vedat Schwenger; Andreas Hamann; Klaus A Dugi; Anne-Marie Schmidt; David Stern; Reinhard Ziegler; Hans U Haering; Martin Andrassy; Fokko van der Woude; Peter P Nawroth Journal: Diabetes Date: 2002-12 Impact factor: 9.461
Authors: C Sassy-Prigent; D Heudes; C Mandet; M F Bélair; O Michel; B Perdereau; J Bariéty; P Bruneval Journal: Diabetes Date: 2000-03 Impact factor: 9.461
Authors: Sydney C W Tang; Loretta Y Y Chan; Joseph C K Leung; Amy Shan Cheng; Kwok Wah Chan; Hui Yao Lan; Kar Neng Lai Journal: Nephrol Dial Transplant Date: 2009-11-18 Impact factor: 5.992
Authors: Caroline Michot; Asmaa Mamoune; Joseph Vamecq; Mai Thao Viou; Lu-Sheng Hsieh; Eric Testet; Jeanne Lainé; Laurence Hubert; Anne-Frédérique Dessein; Monique Fontaine; Chris Ottolenghi; Laetitia Fouillen; Karim Nadra; Etienne Blanc; Jean Bastin; Sophie Candon; Mario Pende; Arnold Munnich; Asma Smahi; Fatima Djouadi; George M Carman; Norma Romero; Yves de Keyzer; Pascale de Lonlay Journal: Biochim Biophys Acta Date: 2013-08-06