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

  • Mol Ther. 2025 Oct 6:S1525-0016(25)00830-5. doi: 10.1016/j.ymthe.2025.10.009.
Yunjie Xiong  1 ,  Ruolin Li  2 ,  Xiangjun Chen  1 ,  Chuan Peng  1 ,  Qinglian Zeng  1 ,  Shuangshuang Zhu  1 ,  Furong He  1 ,  Jinshan Wu  3 ,  Jiangyun Lei  1 ,  Miaoyun Chen  1 ,  Shiyun Tong  1 ,  Yue Sun  1 ,  Yong Xu  4 ,  Wei Huang  4 ,  Shumin Yang  1 ,  Qifu Li  5 ,  Jinbo Hu  6 ,  Linqiang Ma  7
Affiliations
  • 1. Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China.
  • 2. Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China.
  • 3. Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China.
  • 4. Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
  • 5. Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China. Electronic address: [email protected].
  • 6. Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China. Electronic address: [email protected].
  • 7. Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China. Electronic address: [email protected].
PMID: 41054305 DOI: 10.1016/j.ymthe.2025.10.009
Abstract

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.

Keywords
PAD4; cmklr1; diabetic kidney disease; macrophage migration; tubulointerstitial injury.
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