2. Academic Validation
  3. Depletion of CUL4B in macrophages ameliorates diabetic kidney disease via miR-194-5p/ITGA9 axis

Depletion of CUL4B in macrophages ameliorates diabetic kidney disease via miR-194-5p/ITGA9 axis

  • Cell Rep. 2023 May 23;42(6):112550. doi: 10.1016/j.celrep.2023.112550.
Shiqi Jin 1,  Yu Song 1,  Li Zhou 1,  Wei Jiang 1,  Liping Qin 1,  Yufeng Wang 1,  Ruiqi Yu 1,  Yuting Liu 1,  Yujie Diao 2,  Fan Zhang 1,  Kaixuan Liu 3,  Peishan Li 4,  Huili Hu 5,  Baichun Jiang 1,  Wei Tang 6,  Fan Yi 7,  Yaoqin Gong 1,  Guangyi Liu 8,  Gongping Sun 9
Affiliations

Affiliations

  • 1 Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 2 Department of Nephrology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 3 Key Laboratory of Experimental Teratology, Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 4 Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China.
  • 5 Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Systems Biomedicine and Research Center of Stem Cell and Regenerative Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 6 Department of Pathogenic Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 7 Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 8 Department of Nephrology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: guangyi.liu@sdu.edu.cn.
  • 9 Key Laboratory of Experimental Teratology, Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: sgp@sdu.edu.cn.
PMID: 37224018 DOI: 10.1016/j.celrep.2023.112550
Abstract

Diabetic kidney disease (DKD) is the most prevalent chronic kidney disease. Macrophage infiltration in the kidney is critical for the progression of DKD. However, the underlying mechanism is far from clear. Cullin 4B (CUL4B) is the scaffold protein in CUL4B-RING E3 Ligase complexes. Previous studies have shown that depletion of CUL4B in macrophages aggravates lipopolysaccharide-induced peritonitis and septic shock. In this study, using two mouse models for DKD, we demonstrate that myeloid deficiency of CUL4B alleviates diabetes-induced renal injury and fibrosis. In vivo and in vitro analyses reveal that loss of CUL4B suppresses migration, adhesion, and renal infiltration of macrophages. Mechanistically, we show that high glucose upregulates CUL4B in macrophages. CUL4B represses expression of miR-194-5p, which leads to elevated Integrin α9 (ITGA9), promoting migration and adhesion. Our study suggests the CUL4B/miR-194-5p/ITGA9 axis as an important regulator for macrophage infiltration in diabetic kidneys.

Keywords

CP: Immunology; CUL4B; ITGA9; diabetic kidney disease; macrophage infiltration; miR-194-5p.

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