| First Author | Oguiza A | Year | 2015 |
| Journal | Diabetologia | Volume | 58 |
| Issue | 7 | Pages | 1656-67 |
| PubMed ID | 25982245 | Mgi Jnum | J:224789 |
| Mgi Id | MGI:5689072 | Doi | 10.1007/s00125-015-3596-6 |
| Citation | Oguiza A, et al. (2015) Peptide-based inhibition of IkappaB kinase/nuclear factor-kappaB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes. Diabetologia 58(7):1656-67 |
| abstractText | AIMS/HYPOTHESIS: The canonical nuclear factor-kappaB (NF-kappaB) pathway mediated by the inhibitor of NF-kappaB 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-kappaB essential modulator binding domain (NBD) contained in IKKalpha/beta is essential for IKK complex assembly. We therefore investigated the functional consequences of targeting the IKK-dependent NF-kappaB 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 IKKalpha/beta NBD region. Kidneys and aorta were analysed for morphology, leucocyte infiltrate, collagen, NF-kappaB 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-kappaB 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-kappaB-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-kappaB activation, suppresses inflammation and retards the progression of renal and vascular injury in diabetic mice, thus providing a feasible approach against diabetes inflammatory complications. |
