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Am J Physiol Renal Physiol. 2015 Oct 1;309(7):F617-26. doi: 10.1152/ajprenal.00059.2015. Epub 2015 Aug 12.

The NF-κB essential modulator (NEMO) controls podocyte cytoskeletal dynamics independently of NF-κB.

Author information

1
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany;
2
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, Cologne, Germany; and Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany.
3
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; paul.brinkkoetter@uk-koeln.de.

Abstract

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-κB signaling pathway in podocyte cytoskeletal dynamics. As previously published, genetic inhibition of the NF-κB 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 (Brähler 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-α, 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-κB signaling as demonstrated by expression of a mutant IκB resistant to phosphorylation and degradation. In conclusion, signaling through NEMO might not only be involved in the production of NF-κB proinflammatory chemokines but also regulates podocyte dynamics independently of NF-κB, most likely through small GTPases and MAP kinases.

KEYWORDS:

MAPK; NEMO; NF-κB; cytoskeleton; podocyte

PMID:
26268269
DOI:
10.1152/ajprenal.00059.2015
[Indexed for MEDLINE]
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