Targeting peptidylarginine deiminases 2 and 4 in diabetic kidney disease: mechanistic rationale and preclinical evidence.

Abstract

Many patients with diabetic kidney disease (DKD) continue to progress despite guideline-directed quadruple nephroprotective therapy, driven in part by sterile inflammation that current treatment does not target. Peptidylarginine deiminases 2 and 4 (PAD2/4) are calcium-dependent enzymes that convert peptidyl-arginine to peptidyl-citrulline, remodeling chromatin, shaping immune-cell function, and altering extracellular-matrix integrity. In the diabetic kidney, hyperglycemia-associated signaling activates PAD4, driving histone hypercitrullination, neutrophil extracellular trap (NET) formation, and innate-immune cell recruitment, while PAD2 contributes through macrophage-associated citrullination. This review examines PAD2/4 as candidate therapeutic targets in DKD, separating findings with direct evidence in diabetic renal tissue or DKD models from mechanisms extrapolated from rheumatoid arthritis, sepsis, or cancer. Available DKD studies provide early but limited support for a pathogenic role of PAD-mediated citrullination, particularly PAD4-associated NET formation and citrullinated-histone deposition. However, several proposed mechanisms, including citrullination of podocyte cytoskeletal proteins and glycosaminoglycan-driven amplification of PAD4 activity, remain indirect and require validation in diabetic renal tissue. We appraise the isoform-selective inhibitor landscape, candidate pharmacodynamic biomarkers, and translational barriers. In summary, PAD inhibition should therefore be framed as a mechanistically distinct, still-preclinical adjunct to the KDIGO 2024 standard of care, with its renal potential depending on isoform-resolved human data and pharmacokinetic characterization in chronic kidney disease.