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PAD4 Deficiency Limits Kidney Dysregulation in a Murine Model of Shock/Sepsis
Author(s) -
Girard Bethany Biron,
Chen Yaping,
Chung ChunShiang,
Reichner Jonathan Biron,
Ayala Alfred
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.657.16
Subject(s) - ards , neutrophil extracellular traps , acute kidney injury , medicine , sepsis , kidney , lung , septic shock , shock (circulatory) , immunology , inflammation
Indirect Acute Respiratory Distress Syndrome (iARDS) is caused by a non pulmonary inflammatory process as a result from insults such as non‐pulmonary sepsis, hypotensive shock, etc. Patients with ARDS frequently develop Acute Kidney Injury, which in turn, increases overall mortality. Neutrophils are thought to have a significant role in mediating ARDS, with the development of iARDS being characterized by dysregulation and recruitment of activated neutrophils to the lung. PAD4 is an enzyme responsible for the citrullination of histones and subsequent neutrophil extracellular trap (NET) formation. Components of NETs including neutrophil derived circulating free DNA as well as circulating histones has been implicated in ARDS as well as AKI in ischemia/reperfusion injury models. However, it is unknown if there is any pathological significance of NET formation in AKI as a result from a “2 hit” model of traumatic shock (fixed‐pressure hemorrhage; Hem) followed by septic (CLP) insult (Hem/CLP)(iARDS). Previously, we have demonstrated that PAD4 gene deficiency improves overall survival as well as decreases pro‐inflammatory cytokines in the lung in this model of iARDS. Here we aim to determine if PAD4 deficient mice (PAD4−/− mice vs. WT mice) were also protected from AKI in an iARDS model. After Hem/CLP (the induction of iARDS) WT mice displayed increased vascular leakage in the kidney as well as increased circulating Blood Urea Nitrogen (BUN) levels. In contrast, PAD4 −/− mice were protected against increased vascular leakage within the kidney and displayed significant decreases in BUN levels. Conclusion These data taken together suggest that PAD4 deficiency protects against kidney dysfunction associated with ARDS, which in turn contributes to the overall improved survival in the Hem/CLP model of iARDS.