title: Peptidyl arginine deiminase-4-deficient mice are protected against kidney and liver injury after renal ischemia and reperfusion.
abstract: 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.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: May
authors.initials: M
authors.lastname: Rabadi
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: Mihwa
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York.
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; and tl128@columbia.edu.
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Lee
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics*; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D021381:Protein Transport; D000080002:Protein-Arginine Deiminase Type 4; D015427:Reperfusion Injury / Q000235:genetics* / Q000473:pathology*
chemical_list: D016328:NF-kappa B; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse
keywords: NF-κB; acute kidney injury; inflammation; necrosis; peptidyl-citrullination