| First Author | Brähler S | Year | 2015 |
| Journal | Am J Physiol Renal Physiol | Volume | 309 |
| Issue | 7 | Pages | F617-26 |
| PubMed ID | 26268269 | Mgi Jnum | J:280490 |
| Mgi Id | MGI:6368899 | Doi | 10.1152/ajprenal.00059.2015 |
| Citation | Brahler S, et al. (2015) The NF-kappaB essential modulator (NEMO) controls podocyte cytoskeletal dynamics independently of NF-kappaB. Am J Physiol Renal Physiol 309(7):F617-26 |
| abstractText | Maintenance of the glomerular filtration barrier with its fenestrated endothelium, the glomerular basement membrane, and the podocytes as the outer layer, is a major prerequisite for proper renal function. Tight regulation of the balance between plasticity and rigidity of the podocytes' architecture is required to prevent the onset of glomerular disease, mainly proteinuria. The underlying cellular signaling pathways that regulate the organization of the podocytes' cytoskeleton are still a matter of controversial debate. In this study, we investigated the role of the NF-kappaB signaling pathway in podocyte cytoskeletal dynamics. As previously published, genetic inhibition of the NF-kappaB essential modulator (NEMO) in podocytes does not affect glomerular function under physiological, nonstressed conditions nor does it alter the initial podocyte response in an experimental glomerulonephritis (NTN) model (Brahler S, Ising C, Hagmann H, Rasmus M, Hoehne M, Kurschat C, Kisner T, Goebel H, Shankland SJ, Addicks K, Thaiss F, Schermer B, Pasparakis M, Benzing T, Brinkkoetter PT. Am J Physiol Renal Physiol 303: F1473-F1475, 2012). Quite the contrary, podocyte-specific NEMO null mice recovered significantly faster and did not develop glomerulosclerosis and end-stage renal failure over time. Here, we show that cytoskeletal rearrangements and increased podocyte motility following stimulation with IL-1, TNF-alpha, or LPS depend on NEMO. NEMO also regulates the phosphorylation of the MAP kinase ERK1/2 and suppresses the activation of RhoA following stimulation with IL-1. The migratory response and altered ERK1/2 phosphorylation is independent of NF-kappaB signaling as demonstrated by expression of a mutant IkappaB resistant to phosphorylation and degradation. In conclusion, signaling through NEMO might not only be involved in the production of NF-kappaB proinflammatory chemokines but also regulates podocyte dynamics independently of NF-kappaB, most likely through small GTPases and MAP kinases. |
