Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia reperfusion injury.

Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia reperfusion injury. Am J Physiol Renal Physiol. 2014 Aug 27; Authors: Ham A, Rabadi MM, Kim M, Brown KM, Ma Z, D'Agati V, Lee HT Abstract Peptidyl arginine deiminase-4 (PAD4) is a nuclear enzyme that catalyzes the post-translational conversion of arginine residues to citrulline. Post-translational protein citrullination is implicated in several inflammatory autoimmune diseases including rheumatoid arthritis, colitis and multiple sclerosis. Here, we tested the hypothesis that PAD4 contributes to ischemic acute kidney injury (AKI) by exacerbating the inflammatory response after renal ischemia and reperfusion (IR). Renal IR injury in mice increased PAD4 activity as well as PAD4 expression in mouse kidney. After 30 min renal IR, vehicle-treated mice developed severe AKI with large increases in plasma creatinine. In contrast, mice pretreated with PAD4 inhibitors (2-chloroamidine or streptonigrin) had significantly reduced renal IR injury. Further supporting a critical role for PAD4 in generating ischemic AKI, mice pretreated with recombinant human PAD4 (rPAD4) protein and subjected to mild (20 min) renal IR developed exacerbated ischemic AKI. Consistent with the hypothesis that PAD4 regulates renal tubular inflammation after IR, mice treated with a PAD4 inhibitor had significantly reduced renal neutrophil chemotactic cytokine [macrophage inflammatory protein (MIP)-2 and ...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research