Peptidylarginine deiminase 4 is a differential regulator of salt-sensitive and salt-resistant hypertension.

Neutrophils contribute to immune surveillance by releasing neutrophil extracellular traps (NETs) through NETosis. While essential, dysregulated NETosis is linked to pathology. We examined its role in salt-sensitive versus salt-resistant hypertension using Dahl rat models. Hypertensive Dahl S rats, but not normotensive Dahl R rats, showed increased NETosis, higher neutrophil counts, and chronic low-grade inflammation. Inhibiting NETosis with DNase I or by the genetic deletion of peptidyl arginine deiminase (Pad4) exacerbated blood pressure (BP) in S rats, suggesting NETosis protects against salt-sensitive hypertension. Pad4 deletion also caused neutropenia, reduced reactive oxygen species, and exaggerated BP elevation under a high-salt diet. In contrast, Pad4 deletion in R rats lowered systolic BP regardless of diet, indicating NETosis supports BP homeostasis in normotension. These findings highlight the context-dependent role of NETosis in BP regulation, with NETs acting as a protective mechanism in salt-sensitive hypertension.