title: Tubular Epithelial NF-κB Activity Regulates Ischemic AKI.
abstract: NF-κB is a key regulator of innate and adaptive immunity and is implicated in the pathogenesis of AKI. The cell type-specific functions of NF-κB in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue parenchymal cells. We analyzed tubular epithelial-specific NF-κB signaling in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. NF-κB reporter activity and nuclear localization of phosphorylated NF-κB subunit p65 analyses in mice revealed that IRI induced widespread NF-κB activation in renal tubular epithelia and in interstitial cells that peaked 2-3 days after injury. To genetically antagonize tubular epithelial NF-κB activity, we generated mice expressing the human NF-κB super-repressor IκBαΔN 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-κB-dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from IκBαΔN-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-κB activation in renal tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response.
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany; Max Delbrück Center for Molecular Medicine, Berlin, Germany; lajosmarko@yahoo.com dominik.mueller@mdc-berlin.de.
authors.forename: Lajos
authors.initials: L
authors.lastname: Markó
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany;
authors.forename: Emilia
authors.initials: E
authors.lastname: Vigolo
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Hinze
authors.affiliation: Hannover Medical School, Hannover, Germany;
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany;
authors.forename: Giulietta
authors.initials: G
authors.lastname: Roël
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany; Max Delbrück Center for Molecular Medicine, Berlin, Germany;
authors.forename: András
authors.initials: A
authors.lastname: Balogh
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany;
authors.forename: Mira
authors.initials: M
authors.lastname: Choi
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany;
authors.forename: Anne
authors.initials: A
authors.lastname: Wübken
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany; and.
authors.forename: Jimmi
authors.initials: J
authors.lastname: Cording
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany; and.
authors.forename: Ingolf E
authors.initials: IE
authors.lastname: Blasig
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany; Max Delbrück Center for Molecular Medicine, Berlin, Germany;
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany;
authors.forename: Claus
authors.initials: C
authors.lastname: Scheidereit
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany; Department of Nephrology, Charité Medical Faculty, Berlin, Germany.
authors.forename: Kai M
authors.initials: KM
authors.lastname: Schmidt-Ott
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany;
authors.forename: Ruth
authors.initials: R
authors.lastname: Schmidt-Ullrich
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany; Max Delbrück Center for Molecular Medicine, Berlin, Germany;
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Müller
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D007684:Kidney Tubules; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D015427:Reperfusion Injury; D015398:Signal Transduction; D019459:Urothelium
chemical_list: D016328:NF-kappa B
keywords: NF-kappaB; acute renal failure; apoptosis; chemokine; epithelial cells; ischemia-reperfusion; renal tubular
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