Peptidyl arginine deiminase-4-deficient mice are protected against kidney and liver injury after renal ischemia and reperfusion

Am J Physiol Renal Physiol. 2016 Aug 1;311(2):F437-49. doi: 10.1152/ajprenal.00254.2016. Epub 2016 Jun 22.


We previously demonstrated that renal peptidyl arginine deiminase-4 (PAD4) is induced after renal ischemia and reperfusion (I/R) injury and exacerbates acute kidney injury (AKI) by increasing the renal tubular inflammatory response. Here, we tested whether genetic ablation of PAD4 attenuates renal injury and inflammation after I/R in mice. After renal I/R, PAD4 wild-type mice develop severe AKI with large increases in plasma creatinine, neutrophil infiltration, as well as significant renal tubular necrosis, apoptosis, and proinflammatory cytokine generation. In contrast, PAD4-deficient mice are protected against ischemic AKI with reduced real tubular neutrophil infiltration, renal tubular necrosis, and apoptosis. In addition, hepatic injury and inflammation observed in PAD4 wild-type mice after renal I/R are significantly attenuated in PAD4-deficient mice. We also show that increased renal tubular PAD4 expression after renal I/R is associated with translocation of PAD4 from the nucleus to the cytosol. Consistent with PAD4 cytosolic translocation, we show increased renal tubular cytosolic peptidyl-citrullination after ischemic AKI. Mechanistically, recombinant PAD4 treatment increased nuclear translocation of NF-κB in cultured human as well as murine proximal tubule cells that is inhibited by a PAD4 inhibitor (2-chloroamidine). Taken together, our studies further support the hypothesis that renal tubular PAD4 plays a critical role in renal I/R injury by increasing the renal tubular inflammatory response and neutrophil infiltration after renal I/R perhaps by interacting with the proinflammatory transcription factor NF-κB in the cytosol and promoting its nuclear translocation.

Keywords: NF-κB; acute kidney injury; inflammation; necrosis; peptidyl-citrullination.

MeSH terms

  • Acute Kidney Injury / genetics*
  • Acute Kidney Injury / pathology*
  • Animals
  • Cells, Cultured
  • Cytosol / metabolism
  • Humans
  • Hydrolases / antagonists & inhibitors
  • Hydrolases / deficiency*
  • Hydrolases / genetics*
  • Inflammation / genetics
  • Inflammation / pathology
  • Kidney Tubules / metabolism
  • Kidney Tubules, Proximal / metabolism
  • Liver Diseases / genetics*
  • Liver Diseases / pathology*
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Neutrophil Infiltration
  • Protein Transport
  • Protein-Arginine Deiminase Type 4
  • Reperfusion Injury / genetics*
  • Reperfusion Injury / pathology*


  • NF-kappa B
  • Hydrolases
  • Protein-Arginine Deiminase Type 4
  • peptidylarginine deiminase 4, mouse