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Tubular epithelial NF-κB activity regulates ischemic AKI

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Item Type:Article
Title:Tubular epithelial NF-κB activity regulates ischemic AKI
Creators Name:Markó, L. and Vigolo, E. and Hinze, C. and Park, J.K. and Roël, G. and Balogh, A. and Choi, M. and Wübken, A. and Cording, J. and Blasig, I.E. and Luft, F.C. and Scheidereit, C. and Schmidt-Ott, K.M. and 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
Publisher:American Society of Nephrology
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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