PAD4 promotes macrophage migration to aggravate tubulointerstitial injury in diabetic kidney disease.

Peptidyl arginine deiminase 4 (PAD4) is an enzyme predominantly expressed in myeloid cells, and its role in diabetic kidney disease (DKD) remains unknown. We functionally characterized 48 PADI4 variants identified among 469,779 participants from UK Biobank and examined their associations with renal function. We found that most PADI4 variants cause loss of function, which was significantly associated with a higher estimated glomerular filtration rate. We observed an enhanced PAD4 expression in renal tubulointerstitium among DKD patients and animal models of DKD. Both PAD4 deficiency in macrophages and PAD4 inhibitor GSK484 significantly alleviated renal tubulointerstitial injury by reducing macrophage infiltration in diabetic mice models. Mechanistically, PAD4 interacted with p65 to promote its binding to Cmklr1 promoter and induce the expression of Cmklr1, which led to an enhanced macrophage migration. These findings demonstrate the crucial role of PAD4-mediated macrophage migration in tubulointerstitial injury of DKD.