Inhibition of Peptidyl Arginine Deiminase-4 Prevents Renal Ischemia-Reperfusion-Induced Remote Lung Injury

Abstract

Ischemia reperfusion (IR) can lead to acute kidney injury and can be complicated by acute lung injury, which is one of the leading causes of acute kidney injury-related death. Peptidyl arginine deiminase-4 (PAD4) is a member of the PAD enzyme family and plays a critical role in inflammatory reactions and neutrophil extracellular trap formation in a variety of pathological conditions. It has been reported that PAD4 inhibition can protect certain organs from ischemic injury. In this study, we aimed to understand the mode of action of PAD4 in renal ischemia-reperfusion-mediated acute lung injury. Bilateral renal pedicle occlusion was induced for 30 min followed by reperfusion for 24 h. A specific inhibitor of PAD4, GSK484, was delivered via intraperitoneal injection to alter the PAD4 activity. The pulmonary PAD4 expression, pulmonary impairment, neutrophil infiltration, Cit-H3 expression, neutrophil extracellular trap formation, inflammatory cytokine secretion, and pulmonary apoptosis were analyzed. We found that renal ischemia reperfusion was associated with pulmonary pathological changes and increases in neutrophil infiltration, neutrophil extracellular trap formation, and inflammatory cytokine secretion in the lungs of the recipient animals. Suppression of PAD4 by GSK484 reduced remote lung injury by mitigating neutrophil infiltration, neutrophil extracellular trap formation, apoptosis, and inflammatory factor secretion. Our findings demonstrate that specific PAD4 inhibition by GSK484 may be an effective strategy to attenuate distant lung injury complicating renal ischemia-reperfusion injury.

Neutrophils and COVID-19: Active Participants and Rational Therapeutic Targets

“…Promoting chromatin decondensation via the citrullination of histone H3, PAD4 is a major regulator of NET formation ( 239 ). Having shown promise in murine models of infection and inflammation, where inhibition of PAD4 resulted in reduced NET-associated lung injury ( 162 , 240 ), systemic or pulmonary administration of PAD4 inhibitors has been proposed as a potential treatment for severe COVID-19 ( 36 ). Current data that would support such an approach are the results of studies that have shown in vitro treatment with Cl-amidine, an irreversible pan-PAD inhibitor, significantly reduced SARS-CoV-2-induced NET production by HC neutrophils ( 46 ) as well as the enhanced spontaneous NET generation of neutrophils isolated from COVID-19 patients ( 172 ).…”

Neutrophil Extracellular Trap-Driven Occlusive Diseases

“…In addition to their ability to bind and kill pathogens during innate immune responses, neutrophils and NETs participate in inflammatory and coagulatory responses in the circulatory system. So far, occlusions caused by NETs-associated thrombus formation have been linked to cancers [ 16 ], pre-eclampsia [ 63 ], renal ischemia-reperfusion injury [ 64 ], liver pathologies [ 65 ], and severe malaria [ 66 , 67 ].…”

“…This makes PAD4 a possible therapeutic target for the treatment of occlusive NETs-related diseases. The increased activity of PAD4 and the therapeutic potential of its inhibition have already been reported in preclinical settings for the formation of thrombosis [ 22 ], acute pancreatitis [ 81 ], cholelithiasis [ 94 ], meibomian gland disfunction [ 9 ], lung injury [ 64 ], and sickle cell disease [ 56 ].…”

RGD Peptide and PAD4 Inhibitor-Loaded Gold Nanorods for Chemo-Photothermal Combined Therapy to Inhibit Tumor Growth, Prevent Lung Metastasis and Improve Biosafety

“… 1–3 It catalyzes the conversion of arginine from histone to citrulline (citrullination). 4 , 5 Since PAD4 is associated with many human diseases, such as cardiovascular diseases, 6 ischemia-reperfusion (I/R), 7 , 8 neutrophil extracellular traps (NETs), 9 rheumatoid arthritis (RA) 10 and various tumors, 9 , 11 it has attracted the attention of many scientists. A number of reversible and irreversible inhibitors have been synthesized to inhibit the activity of PAD4 and thus prevent the occurrence of various diseases.…”