Integrin α5 Is Regulated by miR-218-5p in Endothelial Progenitor Cells

Abstract

Background Endothelial cell injury is a common nidus of renal injury in patients and consistent with the high prevalence of acute kidney injury reported during the COVID-19 pandemic. This cell type expresses integrin α5 (ITGA5), which is essential to the Tie2 signaling pathway. The micro-RNA miR-218-5p is upregulated in endothelial progenitor cells following hypoxia, but miRNA regulation of Tie2 in the endothelial progenitor cell (EPC) lineage is unclear. Methods We isolated EPCs derived from the human kidney (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 Following 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.

MicroRNA-192-5p downregulates Fat Mass and Obesity-associated Protein to aggravate renal ischemia/reperfusion injury

“…The regulatory network between miR-192-5p and FTO gives us an idea of treating renal injury, and they might be promising targets for renal I/R injury-induced AKI therapy.miRNAs are important in the maintenance of normal cellular functions, and dysregulation of miRNAs can result in a number of pathological states. Several studies have reported that miRNAs regulate angiogenesis, mitochondrial dysfunction, endothelial progenitor cell migration, and glomerular basement membrane structure [ 8 , 9 , 32 , 33 ]. A previous study also reported that miR-192-5p inhibition blocks cell apoptosis in vancomycin-induced HK-2 cells [ 18 ].…”

“…For instance, endothelial-specific miR-17, -18a, -19a, -20a, -19b-1, and -92a-1 knockout promotes renal dysfunction following renal I/R injury through dysfunction of renal microvasculature [ 8 ]. Another study found that miR-218-5p promoted endothelial cell injury to accelerate renal injury [ 9 ]. Kirti et al.…”

Unraveling the Role of Endothelial Dysfunction in Osteonecrosis of the Femoral Head: A Pathway to New Therapies

“…As precursors of endothelial cells, endothelial progenitor cells (EPCs) are derived mainly from peripheral blood and bone marrow [ 37 ]. They play a pivotal role in disorders related to endothelial damage by proliferating, migrating, and differentiating into endothelial cells, in addition to secreting a range of cytokines and vascular growth factors [ 38 ]. Generally, EPCs are separated, based on their morphological traits and culture duration, into two categories: early myeloid angiogenic cells and late endothelial colony-forming cells [ 39 ].…”