Inhibition of IκB Kinase β attenuates hypoxia-induced inflammatory mediators in rat renal tubular cells

These data revealed that hypoxia-induced inflammatory responses were IKKβ/NF-κB-dependent. Knockdown of IKKβ by siRNA suppressed the transcription IKKβ/NF-κB-mediated inflammatory mediators in tumor necrosis factor-α or CoCl(2)-treated tubular epithelial cells, and decreased CoCl(2)-induced cell death, which may be a useful, preventive and therapeutic strategy for ischemic AKI.

Ischemic AKI was induced by a hypoxia-mimicking agent cobalt chloride (CoCl(2)). The therapeutic effects of IKKβ-specific siRNA were evaluated on the expression of interleukin (IL)-18, neutrophil gelatinase-associated lipocalin (NGAL), and cell apoptosis.

Inflammation is now believed to play a major role in the pathophysiology of ischemic acute kidney injury (AKI), which is thought to be directly regulated by nuclear factor-κB (NF-κB). Our previous study indicated that ischemic preconditioning (IPC) alleviated renal ischemic-reperfusion injury due to inhibition of IκB kinase β (IKK β) activity. Using small interfering RNA (siRNA) to silence the expression of IKKβ, which consists of the IKK complex residing at a key convergence site that leads to NF-κB activation in multiple signaling pathways, we protected organs from ischemic AKI. Herein, we have report a siRNA-based treatment to prevent ischemic AKI.

Compared with CoCl(2)-induced NRK52E cells, pretransfected IKKβ-specific siRNA reduced the expression of IL-18 and NGAL to 62.5% and 50.4% in messenger RNA (mRNA) and to 57.2% and 62.7% in protein levels, respectively. The necrosis index in the IKKβ-specific siRNA transfected group was decreased compared with a nonspecific siRNA transfected group. Conclusions: These data revealed that hypoxia-induced inflammatory responses were IKKβ/NF-κB-dependent. Knockdown of IKKβ by siRNA suppressed the transcription IKKβ/NF-κB-mediated inflammatory mediators in tumor necrosis factor-α or CoCl(2)-treated tubular epithelial cells, and decreased CoCl(2)-induced cell death, which may be a useful, preventive and therapeutic strategy for ischemic AKI.