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.
摘要：
糖尿病肾病(DKD)是最常见的慢性肾病。肾脏中的巨噬细胞浸润对于DKD的进展至关重要。然而,潜在的机制还很不清楚。Cullin4B(CUL4B)是CUL4B-RINGE3连接酶复合物中的支架蛋白。先前的研究表明，巨噬细胞中CUL4B的消耗会加重脂多糖诱导的腹膜炎和脓毒性休克。在这项研究中,使用两种DKD小鼠模型，我们证明,髓系CUL4B缺乏可缓解糖尿病诱导的肾损伤和纤维化.体内和体外分析表明，CUL4B的丢失抑制了迁移，附着力,和巨噬细胞的肾脏浸润。机械上,我们显示高糖在巨噬细胞中上调CUL4B.CUL4B抑制miR-194-5p的表达，导致整合素α9（ITGA9）升高，促进迁移和粘附。我们的研究表明CUL4B/miR-194-5p/ITGA9轴是糖尿病肾脏巨噬细胞浸润的重要调节因子。
