Please use this identifier to cite or link to this item: http://hdl.handle.net/10553/75281
Title: Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes
Authors: Oguiza, Ainhoa
Recio Cruz, Carlota Pilar 
Lazaro, Iolanda
Mallavia, Beñat
Blanco, Julia
Egido, Jesus
Gomez-Guerrero, Carmen
UNESCO Clasification: 320502 Endocrinología
Keywords: Atherosclerosis
Diabetes
Inflammation
Nephropathy
Nuclear factor-κB, et al
Issue Date: 2015
Project: SAF2012-38830
PI14/00386
PIE13/00051
FP7-HEALTH-2013-INNOVATION-1-602422
Journal: Diabetologia (Berlin) 
Abstract: Aims/hypothesis The canonical nuclear factor-κB (NF-κB) pathway mediated by the inhibitor of NF-κB kinase (IKK) regulates the transcription of inflammatory genes involved in the pathogenesis of diabetes, from the early phase to progression and final complications. The NF-κB essential modulator binding domain (NBD) contained in IKKα/β is essential for IKK complex assembly. We therefore investigated the functional consequences of targeting the IKK-dependent NF-κB pathway in the progression of diabetes-associated nephropathy and atherosclerosis. Methods Apolipoprotein E-deficient mice with diabetes induced by streptozotocin were treated with a cell-permeable peptide derived from the IKKα/β NBD region. Kidneys and aorta were analysed for morphology, leucocyte infiltrate, collagen, NF-κB activity and gene expression. In vitro studies were performed in renal and vascular cells. Results NBD peptide administration did not affect the metabolic severity of diabetes but resulted in renal protection, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leucocyte infiltration and fibrosis), intranuclear NF-κB activity and proinflammatory and pro-fibrotic gene expression. Furthermore, peptide treatment limited atheroma plaque formation in diabetic mice by decreasing the content of lipids, leucocytes and cytokines and increasing plaque stability markers. This nephroprotective and anti-atherosclerotic effect was accompanied by a decline in systemic T helper 1 cytokines. In vitro, NBD peptide prevented IKK assembly/activation, p65 nuclear translocation, NF-κB-regulated gene expression and cell proliferation induced by either high glucose or inflammatory stimulation. Conclusions/interpretation Peptide-based inhibition of IKK complex formation attenuates NF-κB activation, suppresses inflammation and retards the progression of renal and vascular injury in diabetic mice, thus providing a feasible approach against diabetes inflammatory complications.
URI: http://hdl.handle.net/10553/75281
ISSN: 0012-186X
DOI: 10.1007/s00125-015-3596-6
Source: Diabetologia (Berlin), [ISSN 0012-186X], v. 58, p. 1656–1667
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