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.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Renal and Vascular Inflammation Group, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Avda. Reyes Catolicos, 2, 28040, Madrid, Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Oguiza
authors.forename: Carlota
authors.initials: C
authors.lastname: Recio
authors.forename: Iolanda
authors.initials: I
authors.lastname: Lazaro
authors.forename: Beñat
authors.initials: B
authors.lastname: Mallavia
authors.forename: Julia
authors.initials: J
authors.lastname: Blanco
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.forename: Carmen
authors.initials: C
authors.lastname: Gomez-Guerrero
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry; D007668:Kidney / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000494:pharmacology*; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000187:drug effects; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D010455:Peptides; D051550:I-kappa B Kinase