title: Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury.
abstract: Peptidyl arginine deiminase (PAD)4 is a nuclear enzyme that catalyzes the posttranslational conversion of arginine residues to citrulline. Posttranslational protein citrullination has been 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-reperfusion (I/R). Renal I/R injury in mice increased PAD4 activity as well as PAD4 expression in the mouse kidney. After 30 min of renal I/R, 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 I/R 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 I/R developed exacerbated ischemic AKI. Consistent with the hypothesis that PAD4 regulates renal tubular inflammation after I/R, mice treated with a PAD4 inhibitor had significantly reduced renal neutrophil chemotactic cytokine (macrophage inflammatory protein-2 and keratinocyte-derived cytokine) expression and had decreased neutrophil infiltration. Furthermore, mice treated with rPAD4 had significantly increased renal tubular macrophage inflammatory protein-2 and keratinocyte-derived cytokine expression as well as increased neutrophil infiltration and necrosis. Finally, cultured mouse kidney proximal tubules treated with rPAD4 had significantly increased proinflammatory chemokine expression compared with vehicle-treated cells. Taken together, our results suggest that PAD4 plays a critical role in renal I/R injury by increasing renal tubular inflammatory responses and neutrophil infiltration after renal I/R.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: Ahrom
authors.initials: A
authors.lastname: Ham
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 Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ma
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 / Q000209:etiology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*
chemical_list: D000662:Amphetamines; C032179:2-chloroamphetamine; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; C552151:peptidylarginine deiminase 4, mouse
keywords: acute kidney injury; apoptosis; citrullination; histone; inflammation; necrosis