micro-RNA-486-5p protects against kidney ischemic injury and modifies the apoptotic transcriptome in proximal tubules

Abstract

Acute kidney injury (AKI) carries high morbidity and mortality, and effective treatments are lacking. Preclinical models support involvement of micro-RNAs (miRs) in AKI pathogenesis, although effects on the kidney transcriptome are unclear. We previously showed that injection of cord blood endothelial colony forming cell-derived exosomes, enriched in miR-486-5p, prevented ischemic AKI in mice. To further define this, we studied direct effects of miR-486-5p in mice with kidney ischemia-reperfusion injury. RNA-Seq was used to compare the impact of miR-486-5p and exosomes on the transcriptome of proximal tubules and kidney endothelial cells 24 hours after ischemia-reperfusion. In mice with AKI, injection of miR-486-5p mimic increased its levels in proximal tubules and endothelial cells, and improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis. Additionally, miR-486-5p inhibited expression of its target phosphatase and tensin homolog, and activated protein kinase B. In proximal tubules, miR-486-5p or exosomes reduced expression of genes associated with ischemic injury and the tumor necrosis factor (TNF) pathway, and altered distinct apoptotic genes. In endothelial cells, genes associated with metabolic processes were altered by miR-486-5p or exosomes, although TNF pathway genes were not affected. Thus, our results suggest that miR-486-5p may have therapeutic potential in AKI. Acute kidney injury (AKI) carries high morbidity and mortality, and effective treatments are lacking. Preclinical models support involvement of micro-RNAs (miRs) in AKI pathogenesis, although effects on the kidney transcriptome are unclear. We previously showed that injection of cord blood endothelial colony forming cell-derived exosomes, enriched in miR-486-5p, prevented ischemic AKI in mice. To further define this, we studied direct effects of miR-486-5p in mice with kidney ischemia-reperfusion injury. RNA-Seq was used to compare the impact of miR-486-5p and exosomes on the transcriptome of proximal tubules and kidney endothelial cells 24 hours after ischemia-reperfusion. In mice with AKI, injection of miR-486-5p mimic increased its levels in proximal tubules and endothelial cells, and improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis. Additionally, miR-486-5p inhibited expression of its target phosphatase and tensin homolog, and activated protein kinase B. In proximal tubules, miR-486-5p or exosomes reduced expression of genes associated with ischemic injury and the tumor necrosis factor (TNF) pathway, and altered distinct apoptotic genes. In endothelial cells, genes associated with metabolic processes were altered by miR-486-5p or exosomes, although TNF pathway genes were not affected. Thus, our results suggest that miR-486-5p may have therapeutic potential in AKI. Translational StatementAcute kidney injury is a worldwide health concern that causes substantial morbidity and mortality. Effective treatments to improve kidney function do not exist. Our studies in mice reveal that delivery of microRNA-486-5p protects against ischemia–reperfusion kidney injury, by preserving healthy proximal tubule and endothelial cell gene expression, and by altering genes regulating the tumor necrosis factor pathway and apoptosis in the proximal tubule. These preclinical data support further investigation on the therapeutic potential of microRNA-486-5p in clinically relevant models and highlight the potent effects of microRNA on the kidney transcriptome. Acute kidney injury is a worldwide health concern that causes substantial morbidity and mortality. Effective treatments to improve kidney function do not exist. Our studies in mice reveal that delivery of microRNA-486-5p protects against ischemia–reperfusion kidney injury, by preserving healthy proximal tubule and endothelial cell gene expression, and by altering genes regulating the tumor necrosis factor pathway and apoptosis in the proximal tubule. These preclinical data support further investigation on the therapeutic potential of microRNA-486-5p in clinically relevant models and highlight the potent effects of microRNA on the kidney transcriptome. Acute kidney injury (AKI) due to ischemia–reperfusion (IR) is associated with renal tubular cell necrosis/apoptosis and endothelial cell dysfunction, which contribute importantly to kidney damage.1Basile D.P. The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function.Kidney Int. 2007; 72: 151-156Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar,2Basile D.P. Anderson M.D. Sutton T.A. Pathophysiology of acute kidney injury.Compr Physiol. 2012; 2: 1303-1353Crossref PubMed Scopus (558) Google Scholar AKI has a high prevalence in hospitalized patients,3Negi S. Koreeda D. Kobayashi S. et al.Acute kidney injury: epidemiology, outcomes, complications, and therapeutic strategies.Semin Dial. 2018; 31: 519-527Crossref PubMed Scopus (42) Google Scholar and no treatments are currently available to accelerate kidney repair in humans. MicroRNAs (miRs) are 18-25-nucleotide small RNA species that regulate protein translation via binding to complementary regions of mRNA, usually in the 3′ untranslated region.4Mendell J.T. Olson E.N. MicroRNAs in stress signaling and human disease.Cell. 2012; 148: 1172-1187Abstract Full Text Full Text PDF PubMed Scopus (1227) Google Scholar In preclinical AKI models, several miR variants have been shown to have therapeutic potential.5Brandenburger T. Lorenzen J.M. Diagnostic and therapeutic potential of microRNAs in acute kidney injury.Front Pharmacol. 2020; 11: 657Crossref PubMed Scopus (9) Google Scholar For example, in experimental AKI due to IR, intravenous injection of miR-17-5p mimic prevents histologic ischemic injury and reduces blood urea nitrogen and serum creatinine,6Hao J. Wei Q. Mei S. et al.Induction of microRNA-17-5p by p53 protects against renal ischemia-reperfusion injury by targeting death receptor.Kidney Int. 2017; 91: 106-118Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar and overexpression of miR-21 in mice protects against ischemic kidney injury by reducing apoptosis.7Hu H. Wei J. Xiaoqing X. et al.MicroRNA-21 attenuates renal ischemia reperfusion injury via targeting caspase signaling in mice.Am J Nephrol. 2014; 40: 215-223Crossref PubMed Scopus (38) Google Scholar Preclinical AKI studies have also demonstrated beneficial effects of extracellular vesicles enriched in miRs.8Collino F. Bruno S. Incarnato D. et al.AKI recovery induced by mesenchymal stromal cell-derived extracellular vesicles carrying microRNAs.J Am Soc Nephrol. 2015; 26: 2349-2360Crossref PubMed Scopus (153) Google Scholar,9Ranghino A. Bruno S. Bussolati B. et al.The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury.Stem Cell Res Ther. 2017; 8: 24Crossref PubMed Scopus (78) Google Scholar Microvesicles derived from endothelial progenitor cells protect the kidney by delivering their miR cargo, activating angiogenesis,10Cantaluppi V. Gatti S. Medica D. et al.Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells.Kidney Int. 2012; 82: 412-427Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar and exosomes derived from human mesenchymal stem cells have an antiapoptotic effect in mice with AKI, transferring miR-199a-3p to kidney cells.11Zhu G. Pei L. Lin F. et al.Exosomes from human-bone-marrow-derived mesenchymal stem cells protect against renal ischemia/reperfusion injury via transferring mir-199a-3p.J Cell Physiol. 2019; 234: 23736-23749Crossref PubMed Scopus (45) Google Scholar Regulatory genes and networks associated with injury and repair have been identified in preclinical models of AKI,12Liu J. Krautzberger A.M. Sui S.H. et al.Cell-specific translational profiling in acute kidney injury.J Clin Invest. 2014; 124: 1242-1254Crossref PubMed Scopus (107) Google Scholar, 13Liu J. Kumar S. Dolzhenko E. et al.Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion.JCI Insight. 2017; 2e94716Crossref PubMed Scopus (104) Google Scholar, 14Kumar S. Liu J. McMahon A.P. Defining the acute kidney injury and repair transcriptome.Semin Nephrol. 2014; 34: 404-417Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 15Kumar S. Cellular and molecular pathways of renal repair after acute kidney injury.Kidney Int. 2018; 93: 27-40Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar and modification of the AKI transcriptome by epigenetic or post-transcriptional modification may have therapeutic effects in AKI and chronic kidney disease.16Sharifian R. Okamura D.M. Denisenko O. et al.Distinct patterns of transcriptional and epigenetic alterations characterize acute and chronic kidney injury.Sci Rep. 2018; 8: 17870Crossref PubMed Scopus (14) Google Scholar Although individual miRs may target multiple different genes, the effects of miR delivery on gene expression patterns in ischemic kidney injury remain uncharacterized. We previously demonstrated that cord blood endothelial colony-forming cell (ECFC)-derived exosomes enriched in miR-486-5p were protective against ischemic kidney injury in mice, associated with decreased apoptosis, inhibition of phosphatase and tensin homolog (PTEN) expression, and stimulation of AKT phosphorylation. Interestingly, exosomes derived from ECFCs with knockdown of miR-486-5p did not prevent kidney ischemic injury, supporting a protective role for exosomal transfer of this miR.17Viñas J.L. Burger D. Zimpelmann J. et al.Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury.Kidney Int. 2016; 90: 1238-1250Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar In the present study, we determined the effects of miR-486-5p administration in a mouse model of ischemic kidney injury and compared the impact of miR-486-5p and ECFC-derived exosomes on the transcriptome of proximal tubules (PTs) and endothelial cells. Our results indicate that like exosomes, miR-486-5p delivery prevents ischemic injury, associated with reduction in apoptosis, inhibition of PTEN, and enhanced AKT phosphorylation. Both miR-486-5p and exosomes induce profound in the of and endothelial cells, with a for of gene expression patterns in mice. In gene associated with the tumor necrosis factor (TNF) pathway and apoptosis are altered by miR-486-5p or were from the by previously J.L. Burger D. Zimpelmann J. et al.Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury.Kidney Int. 2016; 90: 1238-1250Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar to mice were by of to the by renal for and of the J.L. Burger D. Zimpelmann J. et al.Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury.Kidney Int. 2016; 90: 1238-1250Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, J.L. A. et in proximal tubule and endothelial gene expression in mice with ischemic acute kidney 2020; PubMed Scopus Google Scholar, J.L. A. et targeting of endothelial colony forming cell-derived exosomes to the kidney after ischemic injury.Sci Rep. 2018; 8: PubMed Scopus Google Scholar, D. J.L. S. et endothelial colony forming cells protect against acute kidney injury: role of J 2015; Full Text Full Text PDF PubMed Scopus Google Scholar The was used to of miR-486-5p mimic or miR from via injection the of The of miR-486-5p was determined in mice exosomes via the of J.L. Burger D. Zimpelmann J. et al.Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury.Kidney Int. 2016; 90: 1238-1250Abstract Full Text Full Text PDF PubMed Scopus (107) Google J.L. A. et targeting of endothelial colony forming cell-derived exosomes to the kidney after ischemic injury.Sci Rep. 2018; 8: PubMed Scopus Google D. J.L. S. et endothelial colony forming cells protect against acute kidney injury: role of J 2015; Full Text Full Text PDF PubMed Scopus Google Scholar mice renal were 24 hours after reperfusion for blood and studies were by the the of and to the of the for creatinine, urea blood urea and were in the were in in and histologic injury neutrophil infiltration, and apoptosis were J.L. Burger D. Zimpelmann J. et al.Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury.Kidney Int. 2016; 90: 1238-1250Abstract Full Text Full Text PDF PubMed Scopus (107) Google J.L. A. et targeting of endothelial colony forming cell-derived exosomes to the kidney after ischemic injury.Sci Rep. 2018; 8: PubMed Scopus Google D. J.L. S. et endothelial colony forming cells protect against acute kidney injury: role of J 2015; Full Text Full Text PDF PubMed Scopus Google Scholar miR-486-5p and miR were by Cell and was on kidney the Cell was on kidney the D. J.L. S. et endothelial colony forming cells protect against acute kidney injury: role of J 2015; Full Text Full Text PDF PubMed Scopus Google Scholar the were and 24 hours after and of was J.L. A. et targeting of endothelial colony forming cell-derived exosomes to the kidney after ischemic injury.Sci Rep. 2018; 8: PubMed Scopus Google Scholar endothelial cells were by and J.L. A. et targeting of endothelial colony forming cell-derived exosomes to the kidney after ischemic injury.Sci Rep. 2018; 8: PubMed Scopus Google Scholar the of genes was in the the are and were of with data were the with For data from mice with miR-486-5p were compared with from mice with with and data from mice with exosomes were compared with from mice with were with was The RNA-Seq data is available from the The RNA-Seq data for mice and mice with kidney with miR-486-5p, or were derived from a data in which we previously compared and kidney after J.L. A. et in proximal tubule and endothelial gene expression in mice with ischemic acute kidney 2020; PubMed Scopus Google Scholar was used to miR-486-5p in mice after IR, with or miR-486-5p exosomes, or for and are in shown in after reperfusion mice with miR-486-5p mimic or exosomes demonstrated increased for miR-486-5p in tubular cells, with to and cells also for miR-486-5p in mice. 24 mice with miR-486-5p injection enhanced for miR-486-5p in kidney compared with miR-486-5p was and in the endothelial cells In we showed by that mice with kidney increased kidney levels of miR-486-5p after injection of J.L. Burger D. Zimpelmann J. et al.Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury.Kidney Int. 2016; 90: 1238-1250Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar In the demonstrated a in kidney levels of miR-486-5p in mice with miR-486-5p after reperfusion shown in 24 hours after reperfusion mice with injection of miR-486-5p mimic demonstrated increased kidney levels of miR-486-5p, which levels after of miR-486-5p also increased in the and after mimic not in the or levels of the and were by miR-486-5p or exosomes 24 hours after IR, miR-486-5p mimic injection induced a in miR-486-5p levels in and endothelial cells exosomes did not miR-486-5p levels in or endothelial cells after 24 with miR-486-5p mimic were against ischemic kidney injury plasma an effect to Both miR-486-5p and exosomes reduced plasma urea although this did not In a protective effect on kidney function and blood urea 24 hours was miR-486-5p mimic was hours after the of reperfusion kidney injury were with miR-486-5p mimic or exosomes a of R. R. et in acute kidney injury: and J Physiol. 2014; PubMed Scopus Google Scholar was decreased after and by with miR-486-5p mimic or exosomes was increased after and decreased by miR-486-5p mimic or exosomes were for histologic of apoptosis, 24 hours after cells increased in with in tubular cells with in and was decreased with miR-486-5p mimic or miR-486-5p mimic or exosomes also inhibited the in in mice with kidney miR-486-5p mimic decreased kidney expression and AKT effects to exosomes In mice, for cells and and cells of the and increased expression in and mice with miR-486-5p mimic or exosomes showed decreased in tubular cells, with RNA-Seq was on and kidney endothelial cells 24 hours after IR, with experimental miR-486-5p mimic in and endothelial cells was of of RNA-Seq data for and endothelial cells, and a to an and from We previously that induced in the transcriptome of and endothelial cells from J.L. A. et in proximal tubule and endothelial gene expression in mice with ischemic acute kidney 2020; PubMed Scopus Google Scholar In the present that miR-486-5p mimic and treatments the transcriptional to a to the in although recovery was in and and In mice with IR, miR also induced in the in although were with miR-486-5p mimic or In mice with IR, administration of miR-486-5p mimic induced genes in compared with miR in associated with AKI were in mice compared with kidney injury neutrophil factor and J. Kumar S. Dolzhenko E. et al.Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion.JCI Insight. 2017; 2e94716Crossref PubMed Scopus (104) Google S. Liu J. McMahon A.P. Defining the acute kidney injury and repair transcriptome.Semin Nephrol. 2014; 34: 404-417Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar miR-486-5p mimic induced in endothelial cells, compared with miR expression of genes associated with endothelial ischemic injury in the miR-486-5p genes of the and H. cells in experimental acute kidney Nephrol. 2015; 11: PubMed Scopus Google Scholar, in renal injury.J Am Soc Nephrol. PubMed Scopus Google Scholar, A. Q. of in acute kidney PubMed Scopus Google Scholar In mice with IR, a of in compared with with miR-486-5p genes associated with AKI were by exosomes and and In endothelial cells, the of was with genes with exosomes compared with with mice, the in from mice with with miR-486-5p mimic In compared with miR induced in and were in from mice with exosomes and and These results suggest of the healthy transcriptome by In to the effect of miR-486-5p mimic on the in endothelial cells the of mice with miR-486-5p, or exosomes of compared with mice and and and In of miR-486-5p gene were by miR-486-5p and exosomes of by In endothelial cells, miR-486-5p gene were in and mice, with no genes for treatments expression of the miR-486-5p target in and was not altered by or treatments 24 hours after IR, in to protein expression that gene expression by in an after expression was decreased by miR-486-5p mimic this was on kidney for genes from and gene from on in expression with and with miR-486-5p mimic or results were in with RNA-Seq data in from mice were enriched in pathways to and were enriched in processes that apoptotic to cell and in with TNF the and In from mice, were associated with and and 24 with the genes for a of processes and pathways the TNF pathway, factor and apoptosis and We in the TNF pathway to miR-486-5p and miR-486-5p mimic exosomes in this of were by treatments and of the of associated with apoptosis in of apoptotic genes with miR-486-5p mimic compared with apoptotic genes compared with IR, and of were to treatments and In endothelial cells, and with miR-486-5p were enriched in processes and pathways to exosomes, in endothelial cells were in and were to and and with miR-486-5p mimic and exosomes were not associated with the TNF pathway, and exosomes showed in to apoptosis. miRs have been in the of AKI and may also have therapeutic potential by targeting genes in injury or T. Lorenzen J.M. Diagnostic and therapeutic potential of microRNAs in acute kidney injury.Front Pharmacol. 2020; 11: 657Crossref PubMed Scopus (9) Google Scholar Our studies reveal that direct delivery of miR-486-5p to mice the of reperfusion protects against kidney injury, to an to administration of ECFC-derived exosomes, which are enriched in this miR.17Viñas J.L. Burger D. Zimpelmann J. et al.Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury.Kidney Int. 2016; 90: 1238-1250Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar effects of miR-486-5p mimic were also with injection hours after was inhibited by which also inhibited expression and activated Both miR-486-5p and exosomes induced in the transcriptome 24 hours after in and endothelial cells, with a for of expression levels in mice and with effects on a of genes the TNF pathway and apoptosis in miR-486-5p levels were in ischemic 24 hours after injection of miR-486-5p not in the or increased and of the miR S. The role of the renal acute kidney Nephrol. 2016; 31: PubMed Scopus Google Scholar miR-486-5p levels also increased in the and which may to the high of and of miR and of the of miRs has been shown to induce L. et and of for gene Clin 2020; Full Text Full Text PDF PubMed Scopus Google X. B. et delivery of and microRNA PubMed Scopus Google Scholar miR-486-5p was and cells after mimic or ECFC-derived Although was after 24 hours in mice with miR-486-5p mimic mice did not enhanced by this Interestingly, after 24 hours exosomes a in kidney levels of miR-486-5p by not in and endothelial cells. These data support the of of miR-486-5p cells, or tubular cells this In studies of mice with kidney injury, we demonstrated increased miR-486-5p levels in and endothelial cells after J.L. A. et targeting of endothelial colony forming cell-derived exosomes to the kidney after ischemic injury.Sci Rep. 2018; 8: PubMed Scopus Google Scholar with the results by an in miR-486-5p levels was in or 24 hours after miR-486-5p mimic injection by and The of miR-486-5p kidney and endothelial cells after mimic is not due to the of miR-486-5p compared with we protective effects of miR-486-5p and exosomes on kidney function and injury after IR, and treatments the healthy transcriptome in and the results suggest that in levels of miR-486-5p after ischemia may protective is an target of J.L. Burger D. Zimpelmann J. et al.Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury.Kidney Int. 2016; 90: 1238-1250Abstract Full Text Full Text PDF PubMed Scopus (107) Google et targeting protects against apoptosis in by activating the J Pharmacol. 2019; PubMed Scopus Google V. et of signaling by A. PubMed Scopus Google Scholar and protein expression was reduced by miR-486-5p or exosomes 24 by and Although gene expression in or endothelial cells was not by miR-486-5p mimic 24 a reduction in kidney gene expression by miR-486-5p mimic was hours after reperfusion by The results suggest that in contribute to decreased protein expression 24 The effects of targeting by miR-486-5p on AKI recovery and transition to chronic kidney remain unclear. In AKI, inhibition of increased kidney after injury, AKI is associated with increased after J. J. Lin S. et of renal in mice with ischemia acute kidney 2017; PubMed Scopus Google Scholar, R. H. et a tubule of and signaling renal J Physiol. 2012; PubMed Scopus Google Scholar, J. S. et of acute kidney 2017; 8: PubMed Scopus Google Scholar administration of or exosomes decreased the expression of several miR-486-5p we that miR-486-5p may for the protective effect In this we and of miR-486-5p by with a on miR-486-5p in human J.L. V. et al.Distinct pathways in the of by 2015; PubMed Scopus Google Scholar for to of miRs and miRs may regulate gene H. Q. et of MicroRNAs in gene and 2018; PubMed Scopus (153) Google Scholar the that miR-486-5p target genes in this The kidney transcriptome in AKI has been the of several J. Krautzberger A.M. Sui S.H. et al.Cell-specific translational profiling in acute kidney injury.J Clin Invest. 2014; 124: 1242-1254Crossref PubMed Scopus (107) Google Scholar, 13Liu J. Kumar S. Dolzhenko E. et al.Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion.JCI Insight. 2017; 2e94716Crossref PubMed Scopus (104) Google Scholar, 14Kumar S. Liu J. McMahon A.P. Defining the acute kidney injury and repair transcriptome.Semin Nephrol. 2014; 34: 404-417Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 15Kumar S. Cellular and molecular pathways of renal repair after acute kidney injury.Kidney Int. 2018; 93: 27-40Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar in gene expression in tubular and endothelial cells with injury and L. Cellular of ischemic acute kidney injury.J Clin Invest. PubMed Scopus Google Scholar and in cell may define the gene networks In our profound in gene expression and and treatments with miR-486-5p or exosomes prevented of a that that of In of genes were by miR-486-5p and exosomes compared with AKI due to is distinct from to D.P. Anderson M.D. Sutton T.A. Pathophysiology of acute kidney injury.Compr Physiol. 2012; 2: 1303-1353Crossref PubMed Scopus (558) Google Scholar and in mice has identified gene with the J. Kumar S. Dolzhenko E. et al.Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion.JCI Insight. 2017; 2e94716Crossref PubMed Scopus (104) Google Scholar hours after ischemic genes and associated with endothelial injury and of protein kinase signaling and of the J 93: Full Text Full Text PDF PubMed Scopus Google Scholar, L. J. T. et to endothelial via in acute injury.Sci Rep. 2015; PubMed Scopus Google Scholar, D. in PubMed Scopus Google Scholar In genes that are 24 hours after reperfusion injury and J. Kumar S. Dolzhenko E. et al.Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion.JCI Insight. 2017; 2e94716Crossref PubMed Scopus (104) Google Scholar with our we gene expression hours after in and endothelial cells in gene expression in cell In kidney is associated with of a that is by of human endothelial cells the of T. T. et of in renal J Physiol. PubMed Scopus Google T. T. et in ischemic acute renal by endothelial J Physiol. PubMed Scopus Google Scholar that endothelial to altered in ischemic kidney injury, and in gene expression to effects may not 24 hours after in the of miR-486-5p target genes by miR-486-5p or exosomes 24 hours was compared with with in the miR-486-5p and exosomes induced of in endothelial cells compared with mice, and the effects of in the transcriptome on function after AKI further In of with treatments after signaling via TNF and apoptosis, which in the of AKI. the TNF pathway is a of J.L. A. et in proximal tubule and endothelial gene expression in mice with ischemic acute kidney 2020; PubMed Scopus Google A. and acute kidney injury.Kidney Int. Full Text Full Text PDF PubMed Scopus Google Scholar, D.P. endothelial in acute kidney ischemia reperfusion 2014; PubMed Scopus Google Scholar, signaling in Clin PubMed Scopus Google Scholar with miR-486-5p or exosomes reduced apoptosis in in in the expression of apoptosis and genes, the gene expression a was the effect of miR on the transcriptome in due to targeting of the to genes. an of of miR in our we identified a distinct of and apoptotic genes by miR-486-5p or exosomes in gene necrosis factor and factor which may relevant or ischemic kidney J. Kumar S. Dolzhenko E. et al.Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion.JCI Insight. 2017; 2e94716Crossref PubMed Scopus (104) Google signaling in Clin PubMed Scopus Google Scholar, R. et necrosis factor and therapeutic potential in kidney J Nephrol. 2012; PubMed Scopus Google Scholar, D.M. et apoptosis via direct with in J PubMed Scopus Google Scholar, et and the and 2016; PubMed Scopus Google Scholar, M.D. kidney proximal tubule Int. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar of our the of and effects of miR-486-5p with exosomes in a model of mouse ischemic kidney injury, and of a data for effects of treatments on cell in AKI We the for effects of miR on the ischemic and potential for of the transcriptome and endothelial cell the results suggest that miR-486-5p has therapeutic potential in ischemic AKI. the no was by to from the of and the of and a from the of The The of the and of the of and the support of are and the and and and data the RNA and the and of the and the results and the with with with with with with with with with with with with with with with with with with with with with with with with

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