Activation of NF-kB via the canonical pathway in nephrotoxic serum nephritis in mice: possible therapeutic applications with specific IKKß / IKK2– inhibition

Abstract

Glomerular diseases are often immune-mediated and the renal infiltration of leukocytes and activation of chemokines play a pivotal role in the pathogenesis of glomeruonephritis. Recent studies have uncovered that the transcription factor nuclear factor-kB (NF-kB) is a key mediator in induction of proinflammatory chemokines and cytokines gene expression in many inflammatory renal diseases. Activation of NF-kB is dependent upon the phosphorylation of its inhibitor, IkBa, by the specific inhibitory kB kinase (IKK) subunit IKK2. We hypothesized that specific antagonism of the NF-kB inflammatory pathway through IKK2 inhibition attenuates glomerulonephritis. Experimental nephrotoxic serum nephritis (NTN) in mice was served as a model of human rapid progressive glomerulonephritis. In the present study we first assessed the characteristics of NF-kB activation in this NTN model and found an oscillation of NF-kB activation with a first peak at day 4 after disease induction and further peaks at days 10 and 21.To further describe the role for IKK2-activation on the course of glomerulonephritis after NTN induction in mice a selective inhibitor of IKK2, COMPOUND A (CpdA) was administered. After 10 days kidney function, glomerular morphology, inflammatory cells infiltration and chemokine expression were determined. Compared with untreated NTN animals the NTN mice pretreated with the IKK2 inhibitor had significant reduction in renal tissue injury. Gel shift experiment and western bloting experiment demonstrated that the translocation of NF-kB was blocked by the IKK2 inhibitor. Interrupted or delayed IKK2-inhibition, however, did not influence renal injury after the induction of NTN. These results therefore suggest that inhibition of IKK2 might be a potential novel therapeutic approach for patients with glomerulonephritis when applicated during the early induction period of the disease not, however, during later stages of the disease. These findings need to be confirmed in additional experimental models of renal inflammatory diseases.