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.

Protective Effect of Nicotinamide Adenine Dinucleotide Phosphate on Renal Ischemia-Reperfusion Injury

“…Tubular necrosis was evaluated in a semi-quantitative manner by determining the percentage of tubules in the external medulla area where epithelial necrosis, loss of the brush border, cast formation, and/or tubular dilation were observed. A five-point scale was used: 0, normal kidney; 1, < 25% tubular necrosis; 2, 25%–50% tubular necrosis; 3, 50%–75% tubular necrosis; and 4, > 75% tubular necrosis [5]. …”

Single cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney

“…NF-κB is a family of inducible transcription factors that share homology in the Rel domain 57 that has been implicated in the inflammatory response in renal disease 58 . In particular, ischemia-reperfusion injury-induced acute kidney injury activates NF-κB and NF-κB inhibition improves renal function 59 . Consistent with this finding, gene set enrichment analysis 60,61 of the differentially expressed genes in PT_VCAM1 compared to PT implicated NF-κB signaling ( Supplementary Fig.…”

Resveratrol Alleviates Inflammatory Responses and Oxidative Stress in Rat Kidney Ischemia-Reperfusion Injury and H2O2-Induced NRK-52E Cells via the Nrf2/TLR4/NF-κB Pathway

“…Due to the reaction to oxidative stress in kidney IRI, the TLR4 signaling pathway is activated and expressed at a high level, causing a severe infiltration of inflammatory cells [20]. Nuclear factor (NF)-κB is an important transcription factor regulating physiological processes, inflammatory responses, and apoptosis [21]. Normally, NF-κB is sequestered in the cytoplasm by the IκB family.…”

“…The IKK complex contains two IκB kinases (IKKα and IKKβ), which are involved in the inflammatory reaction [22]. In some pathological situations, NF-κB is activated by stimuli from immune receptors such as TLRs and antigen receptors, which are upregulated by oxidative and genotoxic stress [21, 23]. Forkhead transcription factor O1 (FoxO1) plays a role not only in regulating metabolism but also in oxidative stress [24, 25].…”