Acute kidney injury (AKI) is characterized by tubular cell death and interstitial inflammation. TWEAK promotes experimental kidney injury and activates the transcription factor NF-κB, a key regulator of genes involved in cell survival and inflammatory response. In search of potential therapeutic targets for AKI, we compared a transcriptomics database of NF-κB-related genes from murine AKI-kidneys with a transcriptomics database of TWEAK-stimulated cultured tubular cells. Four out of twenty-four (17%) genes were significantly upregulated (false discovery rate, FDR<0.05), while nine out of twenty-four (37%) genes were significantly upregulated at FDR <0.1 in both databases. Bcl3 was the top upregulated NF-κB-related gene in experimental AKI and one of the most upregulated genes in TWEAK-stimulated tubular cells. Quantitative reverse transcription PCR (qRT-PCR), western blot and immunohistochemistry confirmed Bcl3 upregulation in both experimental conditions and localized increased Bcl3 expression to tubular cells in AKI. Transcriptomics database analysis revealed increased Bcl3 expression in numerous experimental and human kidney conditions. Furthermore, systemic TWEAK administration increased kidney Bcl3 expression. In cultured tubular cells, targeting Bcl3 by siRNA resulted in the magnification of TWEAK-induced NF-κB transcriptional activity, chemokine upregulation and Klotho downregulation, and in the sensitization to cell death induced by TWEAK/TNFα/interferon-γ. In contrast, Bcl3 overexpression decreased NF-κB transcriptional activity, inflammatory response and cell death while dampening the decrease in Klotho expression. In conclusion, Bcl3 expressed in response to TWEAK stimulation decreases TWEAK-induced inflammatory and lethal responses. Therefore, therapeutic upregulation of Bcl3 activity should be explored in kidney disease because it has advantages over chemical inhibitors of NF-κB that are known to prevent inflammatory responses but can also sensitize the cells to apoptosis.
Acute Kidney Injury* ; Apoptosis ; Blotting, Western ; Cell Death ; Cell Survival ; Down-Regulation ; Humans ; Immunohistochemistry ; Inflammation ; Kidney ; Kidney Diseases ; Polymerase Chain Reaction ; Reverse Transcription ; RNA, Small Interfering ; Transcription Factors ; Up-Regulation