{"doi":"10.1016/j.ajpath.2019.11.014","title":"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 artery–derived EPCs (CD34+/CD105−) 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−/− embryos at E16.5. Mir218-2−/− decreased CD34+ angioblasts in the ureteric bud at E16.5 and were nonviable. Mir218-2+/− 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. 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 artery–derived EPCs (CD34+/CD105−) 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−/− embryos at E16.5. Mir218-2−/− decreased CD34+ angioblasts in the ureteric bud at E16.5 and were nonviable. Mir218-2+/− 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. Ischemia is a leading cause of kidney injury among patients receiving health care in the United States.1Chertow G.M. Burdick E. Honour M. Bonventre J.V. Bates D.W. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients.J Am Soc Nephrol. 2005; 16: 3365-3370Crossref PubMed Scopus (2502) Google Scholar, 2Best P.J. Lennon R. Ting H.H. Bell M.R. Rihal C.S. Holmes D.R. Berger P.B. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions.J Am Coll Cardiol. 2002; 39: 1113-1119Crossref PubMed Scopus (645) Google Scholar, 3Siedlecki A. Irish W. Brennan D.C. Delayed graft function in the kidney transplant.Am J Transplant. 2011; 11: 2279-2296Crossref PubMed Scopus (505) Google Scholar Endothelial cells in the renal vascular system undergo substantial damage and necrosis after an ischemic episode and do not","journal":"American Journal Of Pathology","year":2020,"id":68891,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":364810,"name":"Jialing Liu","orcid":"0000-0002-8242-2455","position":1,"is_corresponding":false},{"id":364811,"name":"Wenqing Yin","orcid":"0000-0001-8123-4228","position":2,"is_corresponding":false},{"id":365807,"name":"Farhiya Abdi","orcid":null,"position":3,"is_corresponding":false},{"id":364812,"name":"Paul Pang","orcid":"0000-0001-7784-2300","position":4,"is_corresponding":false},{"id":364813,"name":"Quynh‐Anh Fucci","orcid":"0000-0002-3126-0716","position":5,"is_corresponding":false},{"id":365808,"name":"Molly Abbott","orcid":null,"position":6,"is_corresponding":false},{"id":15659,"name":"Steven L. Chang","orcid":"0000-0002-7038-5861","position":7,"is_corresponding":false},{"id":364814,"name":"Graeme S. Steele","orcid":"0000-0001-9983-3528","position":8,"is_corresponding":false},{"id":364815,"name":"Ankit Patel","orcid":"0000-0001-6812-1464","position":9,"is_corresponding":false},{"id":364816,"name":"Yutaro Mori","orcid":"0000-0002-8499-5636","position":10,"is_corresponding":false},{"id":364817,"name":"Aifeng Zhang","orcid":"0000-0003-4124-2199","position":11,"is_corresponding":false},{"id":364818,"name":"Shikai Zhu","orcid":"0000-0002-4805-8493","position":12,"is_corresponding":false},{"id":314191,"name":"Tzongshi Lu","orcid":"0000-0002-3115-5000","position":13,"is_corresponding":false},{"id":70178,"name":"Adam S. Kibel","orcid":"0000-0002-9446-7781","position":14,"is_corresponding":false},{"id":364819,"name":"Bin Wang","orcid":"0000-0001-9032-5009","position":15,"is_corresponding":false},{"id":364820,"name":"Kenneth Lim","orcid":"0000-0001-7178-2183","position":16,"is_corresponding":false},{"id":364821,"name":"Andrew M. Siedlecki","orcid":"0000-0002-1789-8609","position":17,"is_corresponding":false},{"id":360613,"name":"Xiaojie Wang","orcid":"0000-0003-4817-5830","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-18T21:41:52.279368Z","pmid":"31972158","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}