miR-218 Expressed in Endothelial Progenitor Cells Contributes to the Development and Repair of the Kidney Microvasculature

Abstract

Ischemia due to hypoperfusion is one of the most common forms of acute kidney injury. We hypothesized that kidney hypoxia initiates the up-regulation of miR-218 expression in endothelial progenitor cells (EPCs) to guide endocapillary repair. Murine renal arteryederived EPCs (CD34 þ /CD105 À ) showed down-regulation of mmu-Mir218-5p/U6 RNA ratio after ischemic injury, while in human renal arteries, MIR218-5p expression was up-regulated after ischemic injury. MIR218 expression was clarified in cell culture experiments in which increases in both SLIT3 and MIR218-2-5p expressions were observed after 5 minutes of hypoxia. ROBO1 transcript, a downstream target of MIR218-2-5p, showed inverse expression to MIR218-2-5p. EPCs transfected with a MIR218-5p inhibitor in three-dimensional normoxic culture showed premature capillary formation. Organized progenitor cell movement was reconstituted when cells were co-transfected with Dicer siRNA and low-dose Mir218-5p mimic. A Mir218-2 knockout was generated to assess the significance of miR-218-2 in a mammalian model. Mir218-2-5p expression was decreased in Mir218-2 À/À embryos at E16.5. Mir218-2 À/À decreased CD34 þ angioblasts in the ureteric bud at E16.5 and were nonviable. Mir218-2 þ/À decreased peritubular capillary density at postnatal day 14 and increased serum creatinine after ischemia in adult mice. Systemic injection of miR-218-5p decreased serum creatinine after injury. These experiments demonstrate that miR-218 expression can be triggered by hypoxia and modulates EPC migration in the kidney.

The miR-199a/214 Cluster Controls Nephrogenesis and Vascularization in a Human Embryonic Stem Cell Model

“…Our data reinforce the idea that considering regulation of the vascularization as predominantly reliant on growth factor (e.g., VEGFA)-receptor interactions is a considerable simplification. This is supported by the recent data from Wang et al. (2020) showing that, although miR-218-2 homozygous knockout mice were not viable, in the heterozygote knockout the density of capillaries was found to be reduced around kidney tubules postnatally.…”

Antagonist targeting miR‑106b‑5p attenuates acute renal injury by regulating renal function, apoptosis and autophagy via the upregulation of TCF4

“…The present study used miR-106b-5p antagonist to treat rats and cells in order to explore the effects of miR-106b-5p inhibition on the regulation of I/R-induced ARI. The main findings were the following: i) In the rats with I/R-induced ARI and RK-52E cells subjected to H/R, miR-106b-5p expression was increased in the renal tissue from rats with ARI and in NRK-52E cells; ii) miR-106b-5p expression targeted the 3'UTR of TcF4 miRNAs have been identified to be crucial modulators in regulating the severity of renal injury in I/R-induced ARI (28,29). Aberrant miRNA expression is closely related to the severity of renal injury and cell apoptosis in kidneys in the progression of ARI (30,31).…”

“…miRNAs have been identified to be crucial modulators in regulating the severity of renal injury in I/R-induced ARI ( 28 , 29 ). Aberrant miRNA expression is closely related to the severity of renal injury and cell apoptosis in kidneys in the progression of ARI ( 30 , 31 ).…”

Integrated Profiling Identifies Key Molecule Drivers as Diagnostic Biomarkers and Therapeutic Targets in Acute Kidney Injury

“…miR-218-5p participates in regulating sepsis-induced acute kidney injury by miR-218-5p/ hemeoxygenase-1 signaling pathway [52]. Wang et al reported that miR-218-5p expressed in endothelial progenitor cells contributes to the development and repair of the kidney microvasculature [53]. miR-485-5p regulates the function of TP53 signaling pathway with signal transduction in response to DNA damage and cell cycle regulation of kidney tissues [54].…”