Integrin α5 Is Regulated by miR-218-5p in Endothelial Progenitor Cells. Issue 3 (March 2022)

• Record Type: Journal Article
• Authors: Liu, Jialing; Li, Yi; Lyu, Lingna; Xiao, Liang; Memon, Aliza A.; Yu, Xin; Halim, Arvin; Patel, Shivani; Osman, Abdikheyre; Yin, Wenqing; Jiang, Jie; Naini, Said; Lim, Kenneth; Zhang, Aifeng; Williams, Jonathan D.; Koester, Ruth; Qi, Kevin Z.; Fucci, Quynh-Anh; Ding, Lai; Chang, Steven; Patel, Ankit; Mori, Yutaro; Chaudhari, Advika; Bao, Aaron; Liu, Jia; Lu, Tzong-Shi; Siedlecki, Andrew
• Is Part Of: Journal of the American Society of Nephrology. Volume 33:Issue 3(2022)
• Page Start: 565
• Page End: 582
• Publication Date: 2022-03
• Subjects: endothelial cells -- renal ischemia
• DOI: 10.1681/ASN.2021020140
• Languages: English
• ISSNs: 1046-6673

Abstract

Significance Statement: Kidney endothelial cells are sensitive to hypoxic injury. This cell type expresses integrin α 5 (ITGA5), which is essential to the Tie2 signaling cascade. The microRNA miR-218 is known to increase after hypoxia, but the microRNA's role in regulating ITGA5 protein synthesis is unclear. In this study, the authors found that miR-218-5p specifically binds to ITGA5 mRNA in human kidney-derived endothelial progenitor cells (EPCs). In an animal model of ischemia/reperfusion injury, cells pretreated with an miR-218-5p mimic were delivered efficiently, whereas an animal model containing an miR-218-2 deletion specific to angioblasts resulted in kidney dysgenesis and impaired migration of mouse kidney-derived EPCs. Understanding the regulation of prominent signaling pathways in EPCs may inform optimization of therapeutic techniques for addressing kidney endothelial cell injury. Visual Abstract: Abstract : Background: Endothelial cell injury is a common nidus of renal injury in patients and consistent with the high prevalence of AKI reported during the coronavirus disease 2019 pandemic. This cell type expresses integrin α 5 (ITGA5), which is essential to the Tie2 signaling pathway. The microRNA miR-218-5p is upregulated in endothelial progenitor cells (EPCs) after hypoxia, but microRNA regulation of Tie2 in the EPC lineage is unclear. Methods: We isolated human kidney-derived EPCs (hkEPCs) and surveyed microRNA target transcripts. A preclinical model of ischemic kidney injury was used to evaluate the effect of hkEPCs on capillary repair. We used a genetic knockout model to evaluate the effect of deleting endogenous expression of miR-218 specifically in angioblasts. Results: After ischemic in vitro preconditioning, miR-218-5p was elevated in hkEPCs. We found miR-218-5p bound to ITGA5 mRNA transcript and decreased ITGA5 protein expression. Phosphorylation of 42/44 MAPK decreased by 73.6% in hkEPCs treated with miR-218-5p. Cells supplemented with miR-218-5p downregulated ITGA5 synthesis and decreased 42/44 MAPK phosphorylation. In a CD309-Cre/miR-218-2-LoxP mammalian model (a conditional knockout mouse model designed to delete pre-miR-218-2 exclusively in CD309 + cells), homozygotes at e18.5 contained avascular glomeruli, whereas heterozygote adults showed susceptibility to kidney injury. Isolated EPCs from the mouse kidney contained high amounts of ITGA5 and showed decreased migratory capacity in three-dimensional cell culture. Conclusions: These results demonstrate the critical regulatory role of miR-218-5p in kidney EPC migration, a finding that may inform efforts to treat microvascular kidney injury via therapeutic cell delivery.