Peptidyl arginine deiminase-4 exacerbates ischemic AKI by finding NEMO (NF κB Essential Modulator).

Peptidyl arginine deiminase-4 exacerbates ischemic AKI by finding NEMO (NFκB Essential Modulator). Am J Physiol Renal Physiol. 2019 Apr 03;: Authors: Rabadi MM, Han SJ, Kim M, D'Agati VD, Lee HT Abstract 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 NFκB activation. However, the mechanisms of PAD4-mediated renal tubular inflammation and NFκB activation after IR remain unclear. Here, we show that recombinant PAD4 preferentially citrullinates recombinant IKKγ (also called NFκB Essential MOdulator or NEMO) over recombinant IKKα or IKKβ . Consistent with this finding, PAD4 citrullinated renal proximal tubular cell IKKγ and promoted NFκB activation via IκBα 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 NFκB inhibition. In vivo, NEMO binding peptide treatment protected against ischemic AKI. Finally, NEMO binding peptide attenuated recombinant PAD4-...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research