Tubular Epithelial NF-κB Activity Regulates Ischemic AKI

[摘要] NF- κ 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- κ B in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue parenchymal cells. We analyzed tubular epithelial-specific NF- κ B signaling in a mouse model of ischemia-reperfusion injury (IRI)–induced AKI. NF- κ B reporter activity and nuclear localization of phosphorylated NF- κ B subunit p65 analyses in mice revealed that IRI induced widespread NF- κ B activation in renal tubular epithelia and in interstitial cells that peaked 2–3 days after injury. To genetically antagonize tubular epithelial NF- κ B activity, we generated mice expressing the human NF- κ B super-repressor I κ B αΔ 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- κ B–dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from I κ B αΔ 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- κ B activation in renal tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response.

[学科分类] 泌尿医学