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

Area of Science:

• Nephrology
• Immunology
• Genetics

Background:

• Diabetic kidney disease (DKD) is a major complication of diabetes, characterized by progressive renal damage.
• The role of Peptidyl arginine deiminase 4 (PAD4), an enzyme in myeloid cells, in DKD pathogenesis is currently unknown.
• Understanding PAD4's function in DKD is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the role of PAD4 in the development and progression of diabetic kidney disease.
• To functionally characterize genetic variants of PAD4 and their association with renal function.
• To elucidate the molecular mechanisms underlying PAD4's contribution to DKD.

Main Methods:

• Functional characterization of 48 PADI4 variants in 469,779 UK Biobank participants.
• Assessment of associations between PADI4 variants and estimated glomerular filtration rate (eGFR).
• Analysis of PAD4 expression in DKD patients and animal models.
• Evaluation of PAD4 deficiency and inhibitor (GSK484) effects in diabetic mouse models.
• Mechanistic studies involving PAD4, p65, and Cmklr1 interactions.

Main Results:

• Most characterized PADI4 variants led to loss of function, significantly associated with higher eGFR.
• PAD4 expression was elevated in the renal tubulointerstitium of DKD patients and models.
• PAD4 deficiency and GSK484 treatment reduced tubulointerstitial injury and macrophage infiltration in diabetic mice.
• PAD4 promotes macrophage migration by interacting with p65 to induce Cmklr1 expression.

Conclusions:

• Loss-of-function PADI4 variants are associated with preserved renal function in a large cohort.
• PAD4 plays a critical role in DKD pathogenesis by enhancing macrophage migration.
• Targeting PAD4 may represent a novel therapeutic strategy for mitigating DKD-associated tubulointerstitial injury.