Tubular epithelial NF-κB activity regulates ischemic AKI

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.