Peptidyl Arginine Deiminase-4 Exacerbates Ischemic AKI by Finding NEMO
Peptidyl arginine deiminase-4 (PAD4) catalyzes the conversion of peptidylarginine residues to peptidylcitrulline. We previously showed that kidney ischemia and reperfusion (IR) injury increases renal proximal tubular PAD4 expression and activity. Furthermore, kidney PAD4 plays a critical role in ischemic acute kidney injury (AKI) injury by promoting renal tubular inflammation, neutrophil infiltration and NFkappaB activation. However, the mechanisms of PAD4-mediated renal tubular inflammation and NFkappaB activation after IR remain unclear. Here, we show that recombinant PAD4 preferentially citrullinates recombinant IKKgamma (also called NFkappaB Essential MOdulator or NEMO) over recombinant IKKalpha or IKKbeta . Consistent with this finding, PAD4 citrullinated renal proximal tubular cell IKKgamma and promoted NFkappaB activation via IkappaBalpha phosphorylation in vitro. NEMO inhibition with a selective NEMO binding peptide attenuated PAD4-mediated pro-inflammatory cytokine mRNA induction in HK-2 cells. Moreover, NEMO inhibition did not affect proximal tubular cell survival, proliferation or apoptosis unlike global NFkappaB inhibition. In vivo, NEMO binding peptide treatment protected against ischemic AKI. Finally, NEMO binding peptide attenuated recombinant PAD4-mediated exacerbation of ischemic AKI, renal tubular inflammation and apoptosis. Taken together, our studies show that PAD4 exacerbates ischemic AKI and inflammation by promoting renal tubular NFkappaB activity and inflammation via NEMO citrullination. Targeting NEMO activation may serve as a potential therapy for this devastating clinical problem.
Rabadi, M., Han, S., Kim, M., D'Agati, V., & Lee, H. (2019). Peptidyl Arginine Deiminase-4 Exacerbates Ischemic AKI by Finding NEMO. American Journal of Physiology.Renal Physiology, 316 (6), F1180-F1190. https://doi.org/10.1152/ajprenal.00089.2019