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| Item Type: | Article |
|---|---|
| Title: | Tubular epithelial NF-κB activity regulates ischemic AKI |
| Creators Name: | Markó, L., Vigolo, E., Hinze, C., Park, J.K., Roël, G., Balogh, A., Choi, M., Wübken, A., Cording, J., Blasig, I.E., Luft, F.C., Scheidereit, C., Schmidt-Ott, K.M., Schmidt-Ullrich, R. and Müller, D.N. |
| Abstract: | NF-{kappa}B is a key regulator of innate and adaptive immunity and is implicated in the pathogenesis of AKI. The cell type-specific functions of NF-{kappa}B in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue parenchymal cells. We analyzed tubular epithelial-specific NF-{kappa}B signaling in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. NF-{kappa}B reporter activity and nuclear localization of phosphorylated NF-{kappa}B subunit p65 analyses in mice revealed that IRI induced widespread NF-{kappa}B activation in renal tubular epithelia and in interstitial cells that peaked 2-3 days after injury. To genetically antagonize tubular epithelial NF-{kappa}B activity, we generated mice expressing the human NF-{kappa}B super-repressor I{kappa}B{alpha}{delta}N in renal proximal, distal, and collecting duct epithelial cells. Compared with control mice, these mice exhibited improved renal function, reduced tubular apoptosis, and attenuated neutrophil and macrophage infiltration after IRI-induced AKI. Furthermore, tubular NF-{kappa}B-dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from I{kappa}B{alpha}{delta}N-expressing mice and exposed to hypoxia-mimetic agent cobalt chloride exhibited less apoptosis and expressed lower levels of chemokines than cells from control mice did. Our results indicate that postischemic NF-{kappa}B activation in renal tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response. |
| Keywords: | Acute Renal Failure, Ischemia-Reperfusion, Chemokine, Renal Tubular, Epithelial Cells, Apoptosis, NF-{kappa}B, Animals, Mice |
| Source: | Journal of the American Society of Nephrology |
| ISSN: | 1046-6673 |
| Publisher: | American Society of Nephrology |
| Volume: | 27 |
| Number: | 9 |
| Page Range: | 2658-2669 |
| Date: | September 2016 |
| Official Publication: | https://doi.org/10.1681/ASN.2015070748 |
| PubMed: | View item in PubMed |
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