Role for NF-kappa B in experimental renal disease
Inflammatory renal disease such as glomerulonephritis and ischemia reperfusion injury are induced by the activation of proinflammatory signaling pathways leading to the production of proinflammatory mediators such as cytokines and chemokines. The increased renal expression of chemoattractants is followed by the recruitment of monocytes/macrophages and T cells into the kidney where they can exert their deleterious effector function.
NF-kappa B is an inducible hetero- or homodimeric transcription factor composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. Five mammalian Rel proteins have been identified so far, NF-kappa B1 (p50 and its precursor p105), NF-kappa B2 (p52 and its precursor p100), c-Rel, RelA (p65), and RelB. NF-kappa B is an important regulator of inflammation and immune responses by mediating pro-inflammatory gene expression including chemokines, cytokines, adhesion molecules and growth factors.
Under basal conditions, NF-κB dimers are retained in the cytoplasm in their inactive form by a family of inhibitory proteins, IκBs, which mask NF-kappa B nuclear localization sites thereby blocking nuclear translocation. NF-kappa B activation occurs via phosphorylation of these inhibitory IκB proteins by the IκB kinase (IKK) complex. The IKK complex, so called signalsome complex, contains three kinases, IKK1 and IKK2 (also known as IKKα and β), as well as a regulatory protein termed NF-κB essential modulator (NEMO/IKKγ) which triggers the classic NF-kappa B activation pathway, which is critical for the activation of resident renal cells such as glomerular endothelial and mesangial cells and tubular epithelial cells but also infiltrating inflammatory cells such as dendritic cells (DCs) and CD4+ T helper (Th) cells during adaptive immune responses.
Thus, the NF-kappa B pathway is widely considered to promote inflammation, and various NF-kappa B inhibitors are currently being tested for the treatment of immune-mediated and inflammatory diseases. Based on these data our group examines whether systemic NF-kappa B inhibition and genetic deletion of IKK1, IKK2 or NEMO in renal cells, lymphocytes and Tregs regulates induction and resolution of experimental kidney injury.
However, as both systemic and cell specific inhibition of the signalsome pathway may aggravate inflammatory renal diseases our findings highlight the need for in vivo studies in which a complex pathway such as NF-kappa B can exert antagonistic functions in different cell types or at different time points. Our findings imply that great care is necessary in clinical studies aiming to treat chronic kidney inflammation by NF-kappa B inhibition.
Therefore, currently our group addresses cell specific regulation of the signalsome complex to better understand the cellular pathophysiological processes underlying kidney injury and repair will hopefully result in the design of more targeted therapies to prevent the injury, improve repair, and minimize chronic progressive kidney disease.
Friedrich Thaiss, Prof. Dr. med.
Linlin Guo, Ph.D.
Meilan Chen, M.D. student
Hannah Heejung Lee, M.D. student
- Leitender Oberarzt
- Zentrum für Innere Medizin
- III. Medizinische Klinik und Poliklinik (Nephrologie/Rheumatologie/Endokrinologie)
- Facharzt für Innere Medizin und Nephrologie