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

Cell reports 2023 Jun 27

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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. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Shiqi Jin, Yu Song, Li Zhou, Wei Jiang, Liping Qin, Yufeng Wang, Ruiqi Yu, Yuting Liu, Yujie Diao, Fan Zhang, Kaixuan Liu, Peishan Li, Huili Hu, Baichun Jiang, Wei Tang, Fan Yi, Yaoqin Gong, Guangyi Liu, Gongping Sun. Depletion of CUL4B in macrophages ameliorates diabetic kidney disease via miR-194-5p/ITGA9 axis. Cell reports. 2023 Jun 27;42(6):112550